The Concise Guide to Pharmacology 2013/14: Transporters

Abstract

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.

Transporters are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.

It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

An Introduction to Transporters

The majority of biological solutes are charged organic or inorganic molecules. Cellular membranes are hydrophobic and, therefore, effective barriers to separate them allowing the formation of gradients, which can be exploited, for example, in the generation of energy. Membrane transporters carry solutes across cell membranes, which would otherwise be impermeable to them. The energy required for active transport processes is obtained from ATP turnover or by exploiting ion gradients.

ATP-driven transporters can be divided into three major classes: P-type ATPases; F-type or V-type ATPases and ATP-binding cassette transporters. The first of these, P-type ATPases, are multimeric proteins, which transport (primarily) inorganic cations. The second, F-type or V-type ATPases, are proton-coupled motors, which can function either as transporters or as motors. Last, are ATP-binding cassette transporters, heavily involved in drug disposition as well as transporting endogenous solutes.

The second largest family of membrane proteins in the human genome, after the G protein-coupled receptors, are the SLC solute carrier family. Within the solute carrier family, there are not only a great variety of solutes transported, from simple inorganic ions to amino acids and sugars to relatively complex organic molecules like haem. The solute carrier family includes 52 families of almost 400 members. Many of these overlap in terms of the solutes that they carry. For example, amino acid accumulation is mediated by members of the SLC1, SLC3/7, SLC6, SLC15, SLC16, SLC17, SLC32, SLC36, SLC38 and SLC43. Further members of the SLC superfamily regulate ion fluxes at the plasma membrane, or solute transport into and out of cellular organelles. Some SLC family members remain orphan transporters, in as much as a physiological function has yet to be determined. Within the SLC superfamily, there is an abundance in diversity of structure. Two families (SLC3 and SLC7) only generate functional transporters as heteromeric partners, where one partner is a single TM domain protein. Membrane topology predictions for other families suggest 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 TM domains. The SLC transporters include members which function as antiports, where solute movement in one direction is balanced by a solute moving in the reverse direction. Symports allow concentration gradients of one solute to allow movement of a second solute across a membrane. A third, relatively small group are equilibrative transporters, which allow solutes to travel across membranes down their concentration gradients. A more complex family of transporters, the SLC27 fatty acid transporters also express enzymatic function. Many of the transporters also express electrogenic properties of ion channels.

Conflict of interest

The authors state that there is no conflict of interest to disclose.

List of records presented

1. 1708 ATP-binding cassette transporter family

2. 1712 F-type and V-type ATPases

3. 1714 P-type ATPases

4. 1717 SLC1 family of amino acid transporters

5. 1719 SLC2 family of hexose and sugar alcohol transporters

6. 1721 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)

7. 1723 SLC4 family of bicarbonate transporters

8. 1724 SLC5 family of sodium-dependent glucose transporters

9. 1728 SLC6 neurotransmitter transporter family

10. 1732 SLC8 family of sodium/calcium exchangers

11. 1733 SLC9 family of sodium/hydrogen exchangers

12. 1734 SLC10 family of sodium-bile acid co-transporters

13. 1736 SLC11 family of proton-coupled metal ion transporters

14. 1737 SLC12 family of cation-coupled chloride transporters

15. 1739 SLC13 family of sodium-dependent sulphate/carboxylate transporters

16. 1740 SLC14 family of facilitative urea transporters

17. 1741 SLC15 family of peptide transporters

18. 1742 SLC16 family of monocarboxylate transporters

19. 1744 SLC17 phosphate and organic anion transporter family

20. 1746 SLC18 family of vesicular amine transporters

21. 1748 SLC19 family of vitamin transporters

22. 1749 SLC20 family of sodium-dependent phosphate transporters

23. 1750 SLC22 family of organic cation and anion transporters

24. 1753 SLC23 family of ascorbic acid transporters

25. 1754 SLC24 family of sodium/potassium/calcium exchangers

26. 1755 SLC25 family of mitochondrial transporters

27. 1760 SLC26 family of anion exchangers

28. 1762 SLC27 family of fatty acid transporters

29. 1763 SLC28 and SLC29 families of nucleoside transporters

30. 1765 SLC30 zinc transporter family

31. 1766 SLC31 family of copper transporters

32. 1767 SLC32 vesicular inhibitory amino acid transporter

33. 1768 SLC33 acetylCoA transporter

34. 1769 SLC34 family of sodium phosphate co-transporters

35. 1770 SLC35 family of nucleotide sugar transporters

36. 1772 SLC36 family of proton-coupled amino acid transporters

37. 1773 SLC37 family of phosphosugar/phosphate exchangers

38. 1774 SLC38 family of sodium-dependent neutral amino acid transporters

39. 1776 SLC39 family of metal ion transporters

40. 1777 SLC40 iron transporter

41. 1778 SLC41 family of divalent cation transporters

42. 1779 SLC42 family of Rhesus glycoprotein ammonium transporters

43. 1780 SLC43 family of large neutral amino acid transporters

44. 1781 SLC44 choline transporter-like family

45. 1782 SLC45 family of putative sugar transporters

46. 1783 SLC46 family of folate transporters

47. 1784 SLC47 family of multidrug and toxin extrusion transporters

48. 1785 SLC48 heme transporter

49. 1786 SLC49 family of FLVCR-related heme transporters

50. 1787 SLC50 sugar transporter

51. 1788 SLC51 family of steroid-derived molecule transporters

52. 1789 SLC52 family of riboflavin transporters

53. 1790 SLCO family of organic anion transporting polypeptides

ATP-binding cassette transporter family

Overview

ATP-binding cassette transporters are ubiquitous membrane proteins characterized by active ATP-dependent movement of a range of substrates, including ions, lipids, peptides, steroids. Individual subunits are typically made up of two groups of 6TM-spanning domains, with two nucleotide-binding domains (NBD). The majority of eukaryotic ABC transporters are ‘full’ transporters incorporating both TM and NBD entities. Some ABCs, notably the ABCD and ABCG families are half-transporters with only a single membrane spanning domain and one NBD, and are only functional as homo- or heterodimers. Eukaryotic ABC transporters convey substrates from the cytoplasm, either out of the cell or into intracellular organelles. Their role in the efflux of exogenous compounds, notably chemotherapeutic agents, has led to considerable interest.

ABCA subfamily

Systematic nomenclature	Common abbreviation	HGNC, UniProt	Comment
ABCA1	ABC1, CERP	ABCA1, O95477	Loss-of-function mutations are associated with Tangier disease, in which plasma HDL cholesterol levels are greatly reduced
ABCA2	ABC2	ABCA2, Q9BZC7	–
ABCA3	ABC3, ABCC	ABCA3, Q99758	Loss-of-function mutations are associated with pulmonary surfactant deficiency
ABCA4	ABCR	ABCA4, P78363	Retinal-specific transporter of N-retinylPE; loss-of-function mutations are associated with Stargardt disease, a juvenile onset macular degenerative disease
ABCA5	–	ABCA5, Q8WWZ7	–
ABCA6	–	ABCA6, Q8N139	–
ABCA7	–	ABCA7, Q8IZY2	Genome wide association studies identify ABCA7 variants as associated with Alzheimer's Disease 6
ABCA8	–	ABCA8, O94911	–
ABCA9	–	ABCA9, Q8IUA7	–
ABCA10	–	ABCA10, Q8WWZ4	–
ABCA12	–	ABCA12, Q86UK0	Reported to play a role in skin ceramide formation 23
ABCA13	–	ABCA13, Q86UQ4	–

Comments

A number of structural analogues are not found in man: ABCA14 (ENSMUSG00000062017); ABCA15 (ENSMUSG00000054746); ABCA16 (ENSMUSG00000051900) and ABCA17 (ENSMUSG00000035435).

ABCB subfamily

Systematic nomenclature	Common abbreviation	HGNC, UniProt	Comment
ABCB1	MDR1, PGP1	ABCB1, P08183	Responsible for the cellular export of many therapeutic drugs. The mouse and rat have two Mdr1 genes (gene names; Mdr1a and Mdr1b) while the human has only the one gene, MDR1
ABCB2	TAP1	TAP1, Q03518	Endoplasmic reticulum peptide transporter, possibly requires heterodimerization with TAP2
ABCB3	TAP2	TAP2, Q03519	Endoplasmic reticulum peptide transporter, possibly requires heterodimerization with TAP1
ABCB4	PGY3	ABCB4, P21439	Transports phosphatidylcholine from intracellular to extracellular face of the hepatocyte canalicular membrane 13
ABCB5	–	ABCB5, Q2M3G0	Multidrug resistance protein in, and marker of, melanoma cells 17
ABCB6	MTABC3	ABCB6, Q9NP58	Putative mitochondrial porphyrin transporter 11; other subcellular localizations are possible, such as the plasma membrane, as a specific determinant of the Langereis blood group system 5
ABCB7	ABC7	ABCB7, O75027	Mitochondrial; reportedly essential for haematopoiesis 15
ABCB8	MABC1	ABCB8, Q9NUT2	Mitochondrial; suggested to play a role in chemoresistance of melanoma 4
ABCB9	TAPL	ABCB9, Q9NP78	Reported to be lysosomal 7
ABCB10	MTABC2	ABCB10, Q9NRK6	Mitochondrial location; the first human ABC transporter to have a crystal structure reported 18
ABCB11	ABC16	ABCB11, O95342	Loss-of-function mutations are associated with progressive familial intrahepatic cholestasis type 2 19

ABCC subfamily

Systematic nomenclature	Common abbreviation	HGNC, UniProt	Comment
ABCC1	MRP1	ABCC1, P33527	Exhibits a broad substrate specificity 1, including LTC4 (Km 97 nM 12) and estradiol-17β-glucuronide 20
ABCC2	MRP2, cMOAT	ABCC2, Q92887	Loss-of-function mutations are associated with Dubin-Johnson syndrome, in which plasma levels of conjugated bilirubin are elevated (OMIM: 237500)
ABCC3	MRP3	ABCC3, O15438	Transports conjugates of glutathione, sulfate or glucuronide 2
ABCC4	MRP4	ABCC4, O15439	Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned 2; reported to export prostaglandins in a manner sensitive to NSAIDS 16
ABCC5	MRP5	ABCC5, O15440	Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned 2
ABCC6	MRP6	ABCC6, O95255	Loss-of-function mutations in ABCC6 are associated with pseudoxanthoma elasticum (OMIM: 264800)
ABCC10	MRP7	ABCC10, Q5T3U5	–
ABCC11	MRP8	ABCC11, Q96J66	Single nucleotide polymorphisms distinguish wet vs. dry earwax (OMIM: 117800); an association between earwax allele and breast cancer risk is reported in Japanese but not European populations
ABCC12	MRP9	ABCC12, Q96J65	–

Comments

ABCC7 (also known as CFTR), a 12TM ABC transporter-type protein, is a cAMP-regulated epithelial cell membrane Cl^- channel involved in normal fluid transport across various epithelia and can be viewed in the Chloride channels section of the Guide ABCC8 (ENSG00000006071, also known as SUR1, sulfonylurea receptor 1) and ABCC9 (ENSG00000069431, also known as SUR2, sulfonylurea receptor 2) are unusual in that they lack transport capacity but regulate the activity of particular K⁺ channels (Kir6.1–6.2), conferring nucleotide sensitivity to these channels to generate the canonical K_ATP channels. ABCC13 (ENSG00000155288) is a possible pseudogene.

ABCD subfamily of peroxisomal ABC transporters

Overview

This family of ‘half-transporters' act as homo- or heterodimers to accumulate fatty acid-CoA esters into peroxisomes for oxidative metabolism 9.

Systematic nomenclature	Common abbreviation	HGNC, UniProt	Comment
ABCD1	ALDP	ABCD1, P33897	Transports coenzyme A esters of very long chain fatty acids 21,22; loss-of-function mutations in ABCD1 are associated with adrenoleukodystrophy (OMIM: 3001002)
ABCD2	ALDR	ABCD2, Q9UBJ2	Coenzyme A esters of very long chain unsaturated fatty acids 22
ABCD3	PMP70	ABCD3, P28288	–

Comments

ABCD4 (ENSG00000119688, also known as PMP69, PXMP1-L or P70R) appears to be located on the endoplasmic reticulum 8, with an unclear function. Loss-of-function mutations in the gene encoding ALDP underlie the metabolic storage disorder X-linked adrenoleukodystrophy.

ABCG subfamily

Overview

This family of ‘half-transporters' act as homo- or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. They are associated with cellular export of sterols and phospholipids, as well as exogenous drugs (ABCG2).

Systematic nomenclature	Common abbreviation	HGNC, UniProt	Comment
ABCG1	ABC8	ABCG1, P45844	Transports sterols and choline phospholipids 10
ABCG2	ABCP	ABCG2, Q9UNQ0	Exhibits a broad substrate specificity, including urate and haem, as well as multiple synthetic compounds 10. The functional transporter is likely to be a homodimer, although higher oligomeric states have also been proposed
ABCG4	–	ABCG4, Q9H172	Putative functional dependence on ABCG1
ABCG5	–	ABCG5, Q9H222	Transports phytosterols and cholesterol; forms an obligate heterodimer with ABCG8. Loss-of-function mutations in ABCG5 are associated with sitosterolemia (OMIM: 210250)
ABCG8	–	ABCG8, Q9H221	Transports phytosterols and cholesterol; forms an obligate heterodimer with ABCG5. Loss-of-function mutations in ABCG8 are associated with sitosterolemia (OMIM: 210250)

Comments

A further group of ABC transporter-like proteins have been identified to lack membrane spanning regions and are not believed to be functional transporters, but appear to have a role in protein translation 3,14: ABCE1 (P61221, also known as OABP or 2'-5' oligoadenylate-binding protein); ABCF1 (Q8NE71, also known as ABC50 or TNF-α-stimulated ABC protein); ABCF2 (Q9UG63, also known as iron-inhibited ABC transporter 2) and ABCF3 (Q9NUQ8).

F-type and V-type ATPases

Overview

The F-type (ATP synthase) and the V-type (vacuolar or vesicular proton pump) ATPases, although having distinct subcellular locations and roles, exhibit marked similarities in subunit structure and mechanism. They are both composed of a ‘soluble’ complex (termed F₁ or V₁) and a membrane complex (F_o or V_o). Within each ATPase complex, the two individual sectors appear to function as connected opposing rotary motors, coupling catalysis of ATP synthesis or hydrolysis to proton transport. Both the F-type and V-type ATPases have been assigned enzyme commission number E.C. 3.6.3.14

F-type ATPase

Overview

The F-type ATPase, also known as ATP synthase or ATP phosphohydrolase (H⁺-transporting), is a mitochondrial membrane-associated multimeric complex consisting of two domains, an F₀ channel domain in the membrane and an F₁ domain extending into the lumen. Proton transport across the inner mitochondrial membrane is used to drive the synthesis of ATP, although it is also possible for the enzyme to function as an ATPase. The ATP5O subunit (oligomycin sensitivity-conferring protein, OSCP, (P48047)), acts as a connector between F₁ and F₀ motors.

The F₁ motor, responsible for ATP turnover, has the subunit composition α3β3γδε.

The F₀ motor, responsible for ion translocation, is complex in mammals, with probably nine subunits centring on A, B, and C subunits in the membrane, together with D, E, F2, F6, G2 and 8 subunits. Multiple pseudogenes for the F₀ motor proteins have been defined in the human genome.

Nomenclature	α subunit	β subunit	γ subunit	δ subunit	ε subunit
HGNC, UniProt	ATP5A1, P25705	ATP5B, P06576	ATP5C1, P36542	ATP5D, P30049	ATP5E, P56381

Nomenclature	A subunit	B subunit	C subunit	D subunit	E subunit	F2 subunit	F6 subunit	G2 subunit	8 subunit
HGNC, UniProt	MT-ATP6, P00846	ATP5F1, P24539	ATP5G1, P05496; ATP5G2, P48201; ATP5G3, Q06055	ATP5H, O75947	ATP5I, P56385	ATP5J2, P56134	ATP5J, P18859	ATP5L2, Q7Z4Y8	MT-ATP8, P03928

V-type ATPase

Overview

The V-type ATPase is most prominently associated with lysosomes in mammals, but also appears to be expressed on the plasma membrane and neuronal synaptic vesicles.

The V₁ motor, responsible for ATP turnover, has eight subunits with a composition of A-H.

TheV_o motor, responsible for ion translocation, has six subunits (a-e).

Nomenclature

A subunit

B1 subunit

B2 subunit

C1 subunit

C2 subunit

D subunit

E1 subunit

E2 subunit

F subunit

G1 subunit

G2 subunit

G3 subunit

H subunit

HGNC, UniProt

ATP6V1A, P38606

ATP6V1B1, P15313

ATP6V1B2, P21281

ATP6V1C1, P21283

ATP6V1C2, Q8NEY4

ATP6V1D, Q9Y5K8

ATP6V1E1, P36543

ATP6V1E2, Q96A05

ATP6V1F, Q16864

ATP6V1G1, O75348

ATP6V1G2, O95670

ATP6V1G3, Q96LB4

ATP6V1H, Q9UI12

Nomenclature	a1 subunit	a2 subunit	a3 subunit	a4 subunit	b subunit	c subunit	d1 subunit	d2 subunit	e1 subunit	e2 subunit
HGNC, UniProt	ATP6V0A1, Q93050	ATP6V0A2, Q9Y487	TCIRG1, Q13488	ATP6V0A4, Q9HBG4	ATP6V0B, Q99437	ATP6V0C, P27449	ATP6V0D1, P61421	ATP6V0D2, Q8N8Y2	ATP6V0E1, O15342	ATP6V0E2, Q8NHE4

P-type ATPases

Overview

Phosphorylation-type ATPases (EC 3.6.3.-) are associated with membranes and the transport of ions or phospholipids. Characteristics of the family are the transient phosphorylation of the transporters at an aspartate residue and the interconversion between E1 and E2 conformations in the activity cycle of the transporters, taken to represent ‘half-channels' facing the cytoplasm and extracellular/luminal side of the membrane, respectively.

Sequence analysis across multiple species allows the definition of five subfamilies, P1-P5. The P1 subfamily includes heavy metal pumps, such as the copper ATPases. The P2 subfamily includes calcium, sodium/potassium and proton/potassium pumps. The P4 and P5 subfamilies include putative phospholipid flippases.

Na+/K+-ATPases (EC 3.6.3.9)

Overview

The cell-surface Na⁺/K⁺-ATPase is an integral membrane protein which regulates the membrane potential of the cell by maintaining gradients of Na⁺ and K⁺ ions across the plasma membrane, also making a small, direct contribution to membrane potential, particularly in cardiac cells. For every molecule of ATP hydrolysed, the Na⁺/K⁺-ATPase extrudes three Na⁺ ions and imports two K⁺ ions. The active transporter is a heteromultimer with incompletely defined stoichiometry, possibly as tetramers of heterodimers, each consisting of one of four large, ten TM domain catalytic α subunits and one of three smaller, single TM domain glycoprotein β-subunits (see table). Additional protein partners known as FXYD proteins (e.g. FXYD2, P54710) appear to associate with and regulate the activity of the pump.

Nomenclature	α1 subunit	α2 subunit	α3 subunit	α4 subunit	β1 subunit	β2 subunit	β3 subunit
HGNC, UniProt	ATP1A1, P05023	ATP1A2, P50993	ATP1A3, P13637	ATP1A4, Q13733	ATP1B1, P05026	ATP1B2, P14415	ATP1B3, P54709

Comments

Na⁺/K⁺-ATPases are inhibited by ouabain and cardiac glycosides, such as digoxin, as well as potentially endogenous cardiotonic steroids 24.

Ca2+-ATPases (EC 3.6.3.8)

Overview

The sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) is an intracellular membrane-associated pump for sequestering calcium from the cytosol into intracellular organelles, usually associated with the recovery phase following excitation of muscle and nerves.

The plasma membrane Ca²⁺-ATPase (PMCA) is a cell-surface pump for extruding calcium from the cytosol, usually associated with the recovery phase following excitation of cells. The active pump is a homodimer, each subunit of which is made up of ten TM segments, with cytosolic C- and N-termini and two large intracellular loops.

Secretory pathway Ca²⁺-ATPases (SPCA) allow accumulation of calcium and manganese in the Golgi apparatus.

Nomenclature	SERCA1	SERCA2	SERCA3
HGNC, UniProt	ATP2A1, O14983	ATP2A2, P16615	ATP2A3, Q93084

Comments

The fungal toxin ochratoxin A has been described to activate SERCA in kidney microsomes 25. cyclopiazonic acid 29, thapsigargin 27 and BHQ are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor 30.

Nomenclature	PMCA1	PMCA2	PMCA3	PMCA4
HGNC, UniProt	ATP2B1, P20020	ATP2B2, Q01814	ATP2B3, Q16720	ATP2B4, P23634

Comments

The stoichiometry of flux through the PMCA differs from SERCA, with the PMCA transporting 1 Ca²⁺ while SERCA transports 2 Ca²⁺.

Nomenclature	SPCA1	SPCA2
HGNC, UniProt	ATP2C1, P98194	ATP2C2, O75185

Comments

Loss-of-function mutations in SPCA1 appear to underlie Hailey-Hailey disease 26.

H+/K+-ATPases (EC 3.6.3.10)

Overview

The H⁺/K⁺ ATPase is a heterodimeric protein, made up of α and β subunits. The α subunit has 10 TM domains and exhibits catalytic and pore functions, while the β subunit has a single TM domain, which appears to be required for intracellular trafficking and stabilising the α subunit. The ATP4A and ATP4B subunits are expressed together, while the ATP12A subunit is suggested to be expressed with the β1 (ATP1B1) subunit of the Na⁺/K⁺-ATPase 28.

Nomenclature	ATP4A	ATP12A	ATP4B
HGNC, UniProt	ATP4A, P20648	ATP12A, P54707	ATP4B, P51164

Comments

The gastric H⁺/K⁺-ATPase is inhibited by proton pump inhibitors used for treating excessive gastric acid secretion, including (R)-lansoprazole and a metabolite of esomeprazole.

Cu+-ATPases (EC 3.6.3.4)

Overview

Copper-transporting ATPases convey copper ions across cell-surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, O00244).

Nomenclature	ATP7A	ATP7B
HGNC, UniProt	ATP7A, Q04656	ATP7B, P35670

Phospholipid-transporting ATPases (EC 3.6.3.1)

Overview

These transporters are thought to translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from one side of the phospholipid bilayer to the other to generate asymmetric membranes. They are also proposed to be involved in the generation of vesicles from intracellular and cell-surface membranes.

Nomenclature

ATP8A1

ATP8A2

ATP8B1

ATP8B2

ATP8B3

ATP8B4

ATP9A

ATP9B

ATP10A

ATP10B

ATP10D

ATP11A

ATP11B

ATP11C

HGNC, UniProt

ATP8A1, Q9Y2Q0

ATP8A2, Q9NTI2

ATP8B1, O43520

ATP8B2, P98198

ATP8B3, O60423

ATP8B4, Q8TF62

ATP9A, O75110

ATP9B, O43861

ATP10A, O60312

ATP10B, O94823

ATP10D, Q9P241

ATP11A, P98196

ATP11B, Q9Y2G3

ATP11C, Q8NB49

Comments

Loss-of-function mutations in ATP8B1 are associated with type I familial intrahepatic cholestasis.

A further series of structurally-related proteins have been identified in the human genome, with as yet undefined function, including ATP13A1 (Q9HD20), ATP13A2 (Q9NQ11), ATP13A3 (Q9H7F0), ATP13A4 (Q4VNC1) and ATP13A5 (Q4VNC0).

SLC1 family of amino acid transporters

Overview

The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 31,37,64,65,76.

Glutamate transporter subfamily

Overview

Glutamate transporters present the unusual structural motif of 8TM segments and 2 re-entrant loops 60. The crystal structure of a glutamate transporter homologue (GltPh) from Pyrococcus horikoshii supports this topology and indicates that the transporter assembles as a trimer, where each monomer is a functional unit capable of substrate permeation 38,78,93 reviewed by 63). This structural data is in agreement with the proposed quaternary structure for EAAT2 55 and several functional studies that propose the monomer is the functional unit 57,67,69,83. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers 74. The activity of glutamate transporters located upon both neurones (predominantly EAAT3, 4 and 5) and glia (predominantly EAAT 1 and 2) serves, dependent upon their location, to regulate excitatory neurotransmission, maintain low ambient extracellular concentrations of glutamate (protecting against excitotoxicity) and provide glutamate for metabolism including the glutamate-glutamine cycle. The Na+/K+-ATPase that maintains the ion gradients that drive transport has been demonstrated to co-assemble with EAAT1 and EAAT2 80. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 54,70. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 36. DA is characterized by excessive excretion of the acidic amino acids glutamate and aspartate and EAAT3 is the predominant glutamate/aspartate transporter in the kidney. Enhanced expression of EAAT2 resulting from administration of β-lactam antibiotics (e.g. ceftriaxone) is neuroprotective and occurs through NF-κB-mediated EAAT2 promoter activation 53,71,81 reviewed by 66). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation 79. In addition, several translational activators of EAAT2 have recently been described 42 along with treatments that increase the surface expression of EAAT2 (e.g. 68; 98), or prevent its down-regulation (e.g. 56). A thermodynamically uncoupled Cl^- flux, activated by Na⁺ and glutamate 59,64,73 (Na⁺ and aspartate in the case of GltPh 82), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability 88,92. Indeed, it has recently been suggested that the primary function of EAAT5 is as a slow anion channel gated by glutamate, rather than a glutamate transporter 52.

Nomenclature	Excitatory amino acid transporter 1	Excitatory amino acid transporter 2	Excitatory amino acid transporter 3	Excitatory amino acid transporter 4	Excitatory amino acid transporter 5
Systematic nomenclature	SLC1A3	SLC1A2	SLC1A1	SLC1A6	SLC1A7
Common abbreviation	EAAT1	EAAT2	EAAT3	EAAT4	EAAT5
HGNC, UniProt	SLC1A3, P43003	SLC1A2, P43004	SLC1A1, P43005	SLC1A6, P48664	SLC1A7, O00341
Endogenous substrates	L-glutamic acid, L-aspartic acid	L-glutamic acid, L-aspartic acid	L-glutamic acid, L-aspartic acid, L-cysteine 94	L-glutamic acid, L-aspartic acid	L-glutamic acid, L-aspartic acid
Substrates	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid
Inhibitors (pIC50)	DL-TBOA (pKB 5.0) 85, UCPH-101 (membrane potential assay) (6.9) 62	DL-TBOA (pKB 6.9) 85, SYM2081 (pKB 5.5) 91, dihydrokainate (pKB 5.0), threo-3-methylglutamate (pKB 4.7) 91, WAY-213613 (6.9)	NBI-59159 (7.6), L-β-BA ([3H]D-aspartate uptake assay) (6.1), DL-TBOA (5.1)	DL-TBOA (pKi 5.4) 84, threo-3-methylglutamate (pKi 4.3) 47	DL-TBOA (pKi 5.5) 84
Radioligands (Kd)	[3H](2S,4R)-4-methylglutamate, [3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (1.55x10−8 M)	[3H](2S,4R)-4-methylglutamate, [3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (1.62x10−8 M)	[3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (3.2x10−7 M)	[3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (2.48x10−8 M)	[3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (2.95x10−8 M)
Stoichiometry	Probably 3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out)	3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out) 72	3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out) 95	Probably 3 Na+: 1 H+: 1 glutamate (in): 1 K+(out)	Probably 3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out)

Comments

The K_B (or K_i) values reported, unless indicated otherwise, are derived from transporter currents mediated by EAATs expressed in voltage-clamped Xenopus laevis oocytes 47,84,85,91. K_B (or K_i) values derived in uptake assays are generally higher (e.g. 85). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)-4-methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (K_M = 54μM; 61,91) and additionally is a potent kainate receptor agonist 97 which renders the compound unsuitable for autoradiographic localisation of EAATs 33. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors 85. WAY-855 and WAY-213613 are both non-substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 45,46. NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10-fold) and EAAT2 (5-fold) 43,44. Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive non-substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 48. [3H](2S,4R)-4-methylglutamate demonstrates low affinity binding (K_D ≅ 6.0 μM) to EAAT1 and EAAT2 in rat brain homogenates 34 and EAAT1 in murine astrocyte membranes 32, whereas [3H]ETB-TBOA binds with high affinity to all EAATs other than EAAT3 86. The novel isoxazole derivative (–)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate 41. threo-3-methylglutamate induces substrate-like currents at EAAT4, but does not elicit heteroexchange of [³H]-aspartate in synaptosome preparations, inconsistent with the behaviour of a substrate inhibitor 47. parawixin 1, a compound isolated from the venom from the spider Parawixia bistriata is a selective enhancer of the glutamate uptake through EAAT2 but not through EAAT1 or EAAT3 50,51. In addition to the agents listed in the table, DL-threo-β-hydroxyaspartate and L-trans-2,4-pyrolidine dicarboxylate act as non-selective competitive substrate inhibitors of all EAATs. Zn²⁺ and arachidonic acid are putative endogenous modulators of EAATs with actions that differ across transporter subtypes (reviewed by 90).

Alanine/serine/cysteine transporter subfamily

Overview

ASC transporters mediate Na⁺-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr and their structure is predicted to be similar to that of the glutamate transporters 35,89. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport 40,96. Whereas EAATs counter-transport K⁺ (see above) ASCTs do not and their function is independent of the intracellular concentration of K⁺ 96.

Nomenclature	Alanine/serine/cysteine transporter 1	Alanine/serine/cysteine transporter 2
Systematic nomenclature	SLC1A4	SLC1A5
Common abbreviation	ASCT1	ASCT2
HGNC, UniProt	SLC1A4, P43007	SLC1A5, Q15758
Endogenous substrates	L-cysteine > L-alanine = L-serine > L-threonine	L-alanine = L-serine = L-cysteine (low Vmax) = L-threonine = L-glutamine = L-asparagine >> L-methionine ≅ glycine ≅ L-leucine > L-valine > L-glutamic acid (enhanced at low pH)
Inhibitors (pIC50)	–	benzylcysteine 58, benzylserine 58, p-nitrophenyl glutamyl anilide 49
Stoichiometry	1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo-, or hetero-exchange; 95)	1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo-, or hetero-exchange; 39)

Comments

The substrate specificity of ASCT1 may extend to L-proline and L-hydroxyproline 77. At low pH (∼5.5) both ASCT1 and ASCT2 are able to exchange acidic amino acids such as L-cysteate and glutamate 87,89. In addition to the inhibitors tabulated above, HgCl₂, methylmercury, mersalyl, at low micromolar concentrations, non-competitively inhibit ASCT2 by covalent modificiation of cysteine residues 75.

SLC2 family of hexose and sugar alcohol transporters

Overview

The SLC2 family transports D-glucose, D-fructose, inositol (e.g. myo-inositol) and related hexoses. Three classes of glucose transporter can be identified, separating GLUT1-4 and 14, GLUT6, 8, 10 and 12; and GLUT5, 7, 9 and 11. Modelling suggests a 12 TM membrane topology, with intracellular termini, with functional transporters acting as homodimers or homotetramers.

Class I transporters

Overview

Class I transporters are able to transport D-glucose, but not D-fructose, in the direction of the concentration gradient and may be inhibited non-selectively by phloretin and cytochalasin B. GLUT1 is the major glucose transporter in brain, placenta and erythrocytes, GLUT2 is found in the pancreas, liver and kidneys, GLUT3 is neuronal and placental, while GLUT4 is the insulin-responsive transporter found in skeletal muscle, heart and adipose tissue. GLUT14 appears to result from gene duplication of GLUT3 and is expressed in the testes 105.

Nomenclature	Glucose transporter 1	Glucose transporter 2	Glucose transporter 3	Glucose transporter 4	Glucose transporter 14
Systematic nomenclature	SLC2A1	SLC2A2	SLC2A3	SLC2A4	SLC2A14
Common abbreviation	GLUT1	GLUT2	GLUT3	GLUT4	GLUT14
HGNC, UniProt	SLC2A1, P11166	SLC2A2, P11168	SLC2A3, P11169	SLC2A4, P14672	SLC2A14, Q8TDB8
Substrates	D-glucose = D-glucosamine 104, dehydroascorbic acid 99	D-glucosamine > D-glucose 104	D-glucose	D-glucosamine ≥ D-glucose 104	–
Radioligands (Kd)	[3H]2-deoxyglucose	[3H]2-deoxyglucose	[3H]2-deoxyglucose	[3H]2-deoxyglucose	–

Class II transporters

Overview

Class II transporters transport D-fructose and appear to be insensitive to cytochalasin B. Class II transporters appear to be predominantly intracellularly located.

Nomenclature	Glucose transporter 6	Glucose transporter 8	Glucose transporter 10	Glucose transporter 12
Systematic nomenclature	SLC2A6	SLC2A8	SLC2A10	SLC2A12
Common abbreviation	GLUT6	GLUT8	GLUT10	GLUT12
HGNC, UniProt	SLC2A6, Q9UGQ3	SLC2A8, Q9NY64	SLC2A10, O95528	SLC2A12, Q8TD20
Substrates	–	D-glucose 101	D-glucose 102, dehydroascorbic acid 102	D-glucose 103

Proton-coupled inositol transporter

Overview

Proton-coupled inositol transporters are expressed predominantly in the brain and can be inhibited by phloretin and cytochalasin B 104.

Nomenclature	Proton myo-inositol cotransporter
Systematic nomenclature	SLC2A13
Common abbreviation	HMIT
HGNC, UniProt	SLC2A13, Q96QE2
Substrates	myo-inositol 104, D-chiro-inositol 104, muco-inositol 104, scyllo-inositol 104
Stoichiometry	1 H+: 1 inositol (in) 100

SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)

Overview

The SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide-linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family).

SLC3 family

Overview

SLC3 family members are single TM proteins with extensive glycosylation of the exterior C-terminus, which heterodimerize with SLC7 family members in the endoplasmic reticulum and assist in the plasma membrane localization of the transporter.

Nomenclature	rBAT	4F2hc
Systematic nomenclature	SLC3A1	SLC3A2
Common abbreviation	rBAT	4F2hc
HGNC, UniProt	SLC3A1, Q07837	SLC3A2, P08195

SLC7 family

Overview

SLC7 family members may be divided into two major groups: cationic amino acid transporters (CATs) and glycoprotein-associated amino acid transporters (gpaATs).

Cationic amino acid transporters are 14 TM proteins, which mediate pH- and sodium-independent transport of cationic amino acids (system y⁺), apparently as an exchange mechanism. These transporters are sensitive to inhibition by N-ethylmaleimide.

Nomenclature	High affinity cationic amino acid transporter 1	Low affinity cationic amino acid transporter 2	Cationic amino acid transporter 3	Cationic amino acid transporter 4	Probable cationic amino acid transporter
Systematic nomenclature	SLC7A1	SLC7A2	SLC7A3	SLC7A4	SLC7A14
Common abbreviation	CAT1	CAT2	CAT3	CAT4	–
HGNC, UniProt	SLC7A1, P30825	SLC7A2, P52569	SLC7A3, Q8WY07	SLC7A4, O43246	SLC7A14, Q8TBB6
Substrates	L-arginine, L-lysine, L-ornithine, L-histidine	L-arginine, L-lysine, L-ornithine, L-histidine	L-arginine, L-lysine, L-ornithine	–	–

Glycoprotein-associated amino acid transporters are 12 TM proteins, which heterodimerize with members of the SLC3 family to act as cell-surface amino acid exchangers.

Nomenclature	L-type amino acid transporter 1	L-type amino acid transporter 2	y+L amino acid transporter 1	y+L amino acid transporter 2	b0,+-type amino acid transporter 1	Asc-type amino acid transporter 1	Cystine/glutamate transporter
Systematic nomenclature	SLC7A5	SLC7A8	SLC7A7	SLC7A6	SLC7A9	SLC7A10	SLC7A11
Common abbreviation	LAT1	LAT2	y+LAT1	y+LAT2	b0,+AT	Asc-1	xCT
HGNC, UniProt	SLC7A5, Q01650	SLC7A8, Q9UHI5	SLC7A7, Q9UM01	SLC7A6, Q92536	SLC7A9, P82251	SLC7A10, Q9NS82	SLC7A11, Q9UPY5

Comments

CAT4 appears to be non-functional in heterologous expression 106, while SLC7A14 has yet to be characterized.

Heterodimers between 4F2hc and LAT1 or LAT2 generate sodium-independent system L transporters. LAT1 transports large neutral amino acids including branched-chain and aromatic amino acids as well as miglustat, whereas LAT2 transports most of the neutral amino acids.

Heterodimers between 4F2hc and y⁺LAT1 or y⁺LAT2 generate transporters similar to the system y⁺L, which transport cationic (L-arginine, L-lysine, L-ornithine) amino acids independent of sodium and neutral (L-leucine, L-isoleucine, L-methionine, L-glutamine) amino acids in a partially sodium-dependent manner. These transporters are N-ethylmaleimide-insensitive. Heterodimers between rBAT and b^0,+AT appear to mediate sodium-independent system b^0,+ transport of most of the neutral amino acids and cationic amino acids (L-arginine, L-lysine and L-ornithine).

Asc-1 appears to heterodimerize with 4F2hc to allow the transport of small neutral amino acids (such as L-alanine, L-serine, L-threonine, L-glutamine and glycine), as well as D-serine, in a sodium-independent manner.

xCT generates a heterodimer with 4F2hc for a system x^-_e-c transporter that mediates the sodium-independent exchange of L-cystine and L-glutamic acid.

AGT has been conjugated with SLC3 members as fusion proteins to generate functional transporters, but the identity of a native heterodimer has yet to be ascertained.

SLC4 family of bicarbonate transporters

Overview

Together with the SLC26 family, the SLC4 family of transporters subserve anion exchange, principally of chloride and bicarbonate (HCO3-), but also carbonate and hydrogen sulphate (HSO4-). SLC4 family members regulate bicarbonate fluxes as part of carbon dioxide movement, chyme neutralization and reabsorption in the kidney.

Within the family, subgroups of transporters are identifiable: the electroneutral sodium-independent Cl^-/HCO₃^- transporters (AE1, AE2 and AE3), the electrogenic sodium-dependent HCO₃^- transporters (NBCe1 and NBCe2) and the electroneutral HCO₃^- transporters (NBCn1 and NBCn2). Topographical information derives mainly from study of AE1, abundant in erythrocytes, which suggests a dimeric or tetrameric arrangement, with subunits made up of 13 TM domains and re-entrant loops at TM9/10 and TM11/12. The N terminus exhibits sites for interaction with multiple proteins, including glycolytic enzymes, haemoglobin and cytoskeletal elements.

Anion exchangers

Nomenclature	Anion exchange protein 1	Anion exchange protein 2	Anion exchange protein 3	Anion exchange protein 4
Systematic nomenclature	SLC4A1	SLC4A2	SLC4A3	SLC4A9
Common abbreviation	AE1	AE2	AE3	AE4
HGNC, UniProt	SLC4A1, P02730	SLC4A2, P04920	SLC4A3, P48751	SLC4A9, Q96Q91
Endogenous substrates	Cl-, HCO3-	Cl-, HCO3-	Cl-, HCO3-	–
Stoichiometry	1 Cl- (in): 1 HCO3- (out)	1 Cl- (in): 1 HCO3- (out)	1 Cl- (in): 1 HCO3- (out)	–

Sodium-dependent HCO3- transporters

Nomenclature	Electrogenic sodium bicarbonate cotransporter 1	Electrogenic sodium bicarbonate cotransporter 4	Electroneutral sodium bicarbonate cotransporter 1	Electroneutral sodium bicarbonate cotransporter 2	NBCBE	NaBC1
Systematic nomenclature	SLC4A4	SLC4A5	SLC4A7	SLC4A10	SLC4A8	SLC4A11
Common abbreviation	NBCe1	NBCe2	NBCn1	NBCn2	NDCBE	BTR1
HGNC, UniProt	SLC4A4, Q9Y6R1	SLC4A5, Q9BY07	SLC4A7, Q9Y6M7	SLC4A10, Q6U841	SLC4A8, Q2Y0W8	SLC4A11, Q8NBS3
Endogenous substrates	NaHCO3-	NaHCO3-	NaHCO3-	NaHCO3-	Cl-, NaHCO3-	Cl-, NaHCO3-
Stoichiometry	1 Na+: 2/3 HCO3- (out) or 1 Na+: CO32*	1 Na+: 2/3 HCO3- (out) or 1 Na+: CO32*	1 Na+: 1 HCO3- (out) or 1 Na+: CO32*	1 Na+: 1 HCO3- (out) or 1 Na: CO32*	1 Na+: 2HCO3- (in): 1 Cl- (out)	–

SLC5 family of sodium-dependent glucose transporters

Overview

The SLC5 family of sodium-dependent glucose transporters includes, in mammals, the Na⁺/substrate co-transporters for glucose (e.g. choline), D-glucose, monocarboxylates, myo-inositol and I^- 121,122,142,143. Members of the SLC5 and SLC6 families, along with other unrelated Na⁺ cotransporters (i.e. Mhp1 and BetP), share a common structural core that contains an inverted repeat of 5TM α-helical domains 107.

Hexose transporter family

Overview

Detailed characterisation of members of the hexose transporter family is limited to SGLT1, 2 and 3, which are all inhibited in a competitive manner by phlorizin, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see 142 for an extensive review). SGLT1 is predominantly expressed in the small intestine, mediating the absorption of glucose (e.g. D-glucose), but also occurs in the brain, heart and in the late proximal straight tubule of the kidney. The expression of SGLT2 is almost exclusively restricted to the early proximal convoluted tubule of the kidney, where it is largely responsible for the renal reabsorption of glucose. SGLT3 is not a transporter but instead acts as a glucosensor generating an inwardly directed flux of Na⁺ that causes membrane depolarization 117.

Nomenclature	SGLT1	SGLT2	SGLT3	SGLT4	SGLT5
Systematic nomenclature	SLC5A1	SLC5A2	SLC5A4	SLC5A9	SLC5A10
Common abbreviation	SGLT1	SGLT2	SGLT3	SGLT4	SGLT5
HGNC, UniProt	SLC5A1, P13866	SLC5A2, P31639	SLC5A4, Q9NY91	SLC5A9, Q2M3M2	SLC5A10, A0PJK1
Substrates	D-glucose, α-MDG, D-galactose	D-glucose, α-MDG	D-glucose, N-ethyl-1-deoxynojirimycin, 1-deoxynojirimycin, 1-deoxynojirimycin-1-sulfonic acid, miglustat, miglitol	D-glucose, α-MDG, D-mannose	D-glucose, D-galactose
Inhibitors (pIC50)	remogliflozin (pKi 5.4), sergliflozin (pKi 5.1), canagliflozin (6.4), dapagliflozin (5.9), empagliflozin (5.1)	remogliflozin (pKi 7.9), sergliflozin (pKi 6.8), dapagliflozin (9.0), canagliflozin (8.7), empagliflozin (8.5)	–	–	–
Stoichiometry	2 Na+: 1 glucose 129	1 Na+: 1 glucose 127	–	–	–

Comments

Recognition and transport of substrate by SGLTs requires that the sugar is a pyranose. De-oxyglucose derivatives have reduced affinity for SGLT1, but the replacement of the sugar equatorial hydroxyl group by fluorine at some positions, excepting C2 and C3, is tolerated (see 142 for a detailed quantification). Although SGLT1 and SGLT2 have been described as high- and low-affinity sodium glucose co-transporters, respectively, recent work suggests that they have a similar affinity for glucose under physiological conditions 127. Selective blockers of SGLT2, and thus blocking ∼50% of renal glucose reabsorption, are in use and in further development for the treatment of diabetes (e.g. 113).

Choline transporter

Overview

The high affinity, hemicholinium-3-sensitive, choline transporter (CHT) is expressed mainly in cholinergic neurones on nerve cell terminals and synaptic vesicles (keratinocytes being an additional location). In autonomic neurones, expression of CHT requires an activity-dependent retrograde signal from postsynaptic neurones 130. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal 121. Homozygous mice engineered to lack CHT die within one hour of birth as a result of hypoxia arising from failure of transmission at the neuromuscular junction of the skeletal muscles that support respiration 120. A low affinity choline uptake mechanism that remains to be identified at the molecular level may involve multiple transporters. In addition, a family of choline transporter-like (CTL) proteins, (which are members of the SLC44 family) with weak Na⁺ dependence have been described 140.

Nomenclature	CHT
Systematic nomenclature	SLC5A7
Common abbreviation	CHT
HGNC, UniProt	SLC5A7, Q9GZV3
Endogenous substrates	choline
Substrates	triethylcholine
Selective inhibitors (pIC50)	hemicholinium-3 (pKi 8.3 – 9.0)
Radioligands (Kd)	[3H]hemicholinium-3 (4x10-9 – 6x10-9 M)
Stoichiometry	Na+: choline (variable stoichimetry); modulated by extracellular Cl- 128

Comments

K_i and K_D values for hemicholinium-3 listed in the table are for human CHT expressed in Xenopus laevis oocytes 133, or COS-7 cells 109. hemicholinium mustard is a substrate for CHT that causes covalent modification and irreversible inactivation of the transporter. Several exogenous substances (e.g. triethylcholine) that are substrates for CHT act as precursors to cholinergic false transmitters.

Sodium iodide symporter, sodium-dependent multivitamin transporter and sodium-coupled monocarboxylate transporters

Overview

The sodium-iodide symporter (NIS) is an iodide transporter found principally in the thyroid gland where it mediates the accumulation of I^- within thyrocytes. Transport of I^- by NIS from the blood across the basolateral membrane followed by apical efflux into the colloidal lumen, mediated at least in part by pendrin (SLC22A4), and most likely not SMCT1 (SLC5A8) as once thought, provides the I^- required for the synthesis of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) 111. NIS is also expressed in the salivary glands, gastric mucosa, intestinal enterocytes and lactating breast. NIS mediates I^- absorption in the intestine and I^- secretion into the milk. SMVT is expressed on the apical membrane of intestinal enterocytes and colonocytes and is the main system responsible for biotin (vitamin H) and pantothenic acid (vitamin B₅) uptake in humans 135. SMVT located in kidney proximal tubule epithelial cells mediates the reabsorption of biotin and pantothenic acid. SMCT1 (SLC5A8), which transports a wide range of monocarboxylates, is expressed in the apical membrane of epithelia of the small intestine, colon, kidney, brain neurones and the retinal pigment epithelium 122. SMCT2 (SLC5A12) also localises to the apical membrane of kidney, intestine, and colon, but in the brain and retina is restricted to astrocytes and Müller cells, respectively 122. SMCT1 is a high-affinity transporter whereas SMCT2 is a low-affinity transporter. The physiological substrates for SMCT1 and SMCT2 are lactate (L-lactic acid and D-lactic acid), pyruvic acid, propanoic acid, and nicotinic acid in non-colonic tissues such as the kidney. SMCT1 is also likely to be the principal transporter for the absorption of nicotinic acid (vitamin B₃) in the intestine and kidney 124. In the small intestine and colon, the physiological substrates for these transporters are nicotinic acid and the short-chain fatty acids acetic acid, propanoic acid, and butyric acid that are produced by bacterial fermentation of dietary fiber 132. In the kidney, SMCT2 is responsible for the bulk absorption of lactate because of its low-affinity/high-capacity nature. Absence of both transporters in the kidney leads to massive excretion of lactate in urine and consequently drastic decrease in the circulating levels of lactate in blood 138. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non-colonic tissues 123. The tumour-suppressive function of SMCT1 is based on its ability to transport pyruvic acid, an inhibitor of histone deacetylases, into cells in non-colonic tissues 139; in the colon, the ability of SMCT1 to transport butyric acid and propanoic acid, also inhibitors of histone deacetylases, underlies the tumour-suppressive function of this transporter 122,123,125. The ability of SMCT1 to promote histone acetylase inhibition through accumulation of butyric acid and propanoic acid in immune cells is also responsible for suppression of dendritic cell development in the colon 137.

Nomenclature	NIS	SMVT	SMCT1	SMCT2
Systematic nomenclature	SLC5A5	SLC5A6	SLC5A8	SLC5A12
Common abbreviation	NIS	SMVT	SMCT1	SMCT2
HGNC, UniProt	SLC5A5, Q92911	SLC5A6, Q9Y289	SLC5A8, Q8N695	SLC5A12, Q1EHB4
Substrates	NO3-, pertechnetate, perchlorate, thiocyanate, I-	pantothenic acid 116, I- 116, biotin 116, lipoic acid 116	acetic acid, butyric acid, propanoic acid, nicotinic acid, β-D-hydroxybutyric acid, L-lactic acid, D-lactic acid, salicylic acid, 3-bromopyruvate, dichloroacetate, 2-oxothiazolidine-4-carboxylate, acetoacetic acid, benzoate, 5-aminosalicylate, α-ketoisocaproate, β-L-hydroxybutyric acid, pyroglutamic acid, γ-hydroxybutyric acid, pyruvic acid	nicotinic acid, L-lactic acid, pyruvic acid
Inhibitors (pIC50)	–	–	fenoprofen, ketoprofen, ibuprofen (4.2)	–
Stoichiometry	2Na+: 1 I- 119; 1Na+: 1 ClO4- 118	2Na+: 1 biotin (or pantothenic acid) 134	2Na+: 1 monocarboxylate 114	–

Comments

I^-, perchlorate, thiocyanate and NO3- are competitive substrate inhibitors of NIS 118. lipoic acid appears to act as a competitive substrate inhibitor of SMVT 141 and the anticonvulsant drugs primidone and carbamazepine competitively block the transport of biotin by brush border vesicles prepared from human intestine 136.

Sodium myo-inositol cotransporter transporters

Overview

Three different mammalian myo-inositol cotransporters are currently known; two are the Na⁺-coupled SMIT1 and SMIT2 tabulated below and the third is proton-coupled HMIT (SLC2A13). SMIT1 and SMIT2 have a widespread and overlapping tissue location but in polarized cells, such as the Madin-Darby canine kidney cell line, they segregate to the basolateral and apical membranes, respectively 110. In the nephron, SMIT1 mediates myo-inositol uptake as a ‘compatible osmolyte’ when inner medullary tubules are exposed to increases in extracellular osmolality, whilst SMIT2 mediates the reabsorption of myo-inositol from the filtrate. In some species (e.g. rat, but not rabbit) apically located SMIT2 is responsible for the uptake of myo-inositol from the intestinal lumen 108.

Nomenclature	SMIT	SGLT6
Systematic nomenclature	SLC5A3	SLC5A11
Common abbreviation	SMIT1	SMIT2
HGNC, UniProt	SLC5A3, P53794	SLC5A11, Q8WWX8
Substrates	myo-inositol, scyllo-inositol > L-fucose > L-xylose > L-glucose, D-glucose, α-methyl-D-glucopyranoside > D-galactose, D-fucose > D-xylose 126	myo-inositol = D-chiro-inositol> D-glucose > D-xylose > L-xylose 115
Inhibitors (pIC50)	phlorizin	phlorizin
Stoichiometry	2 Na+ :1 myo-inositol 126	2 Na+ :1 myo-inositol 112

Comments

The data tabulated are those for dog SMIT1 and rabbit SMIT2. SMIT2 transports D-chiro-inositol, but SMIT1 does not. In addition, whereas SMIT1 transports both D-xylose and L-xylose and D-fucose and L-fucose, SMIT2 transports only the D-isomers of these sugars 115,126. Thus the substrate specificities of SMIT1 (for L-fucose ) and SMIT2 (for D-chiro-inositol) allow discrimination between the two SMITs. Human SMIT2 appears not to transport glucose 131.

SLC6 neurotransmitter transporter family

Overview

Members of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters 152,156,179 are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters 189. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuT_Aa, a Na⁺-dependent amino acid transporter from Aquiflex aeolicus 206 and in several other transporter families structurally related to LeuT 164.

Monoamine transporter subfamily

Overview

Monoamine neurotransmission is limited by perisynaptic transporters. Presynaptic monoamine transporters allow recycling of synaptically released noradrenaline, dopamine and 5-hydroxytryptamine (5-HT).

Nomenclature	Noradrenaline transporter	Dopamine transporter	5HT transporter
Systematic nomenclature	SLC6A2	SLC6A3	SLC6A4
Common abbreviation	NET	DAT	SERT
HGNC, UniProt	SLC6A2, P23975	SLC6A3, Q01959	SLC6A4, P31645
Endogenous substrates	(-)-adrenaline, (-)-noradrenaline, dopamine	(-)-adrenaline, (-)-noradrenaline, dopamine	5-HT
Substrates	MPP+, methamphetamine, amphetamine	MPP+, methamphetamine, amphetamine	MDMA, p-chloroamphetamine
Selective inhibitors (pIC50)	mazindol (pKi 8.9), nisoxetine (pKi 8.4), nomifensine (pKi 8.1), reboxetine (pKi 8.0) 205	mazindol (pKi 8.0), WIN35428 (pKi 7.9), GBR12935 (pKi 7.6)	paroxetine (pKi 9.6) 198, sertraline (pKi 9.1), fluoxetine (pKi 8.5) 198
Radioligands (Kd)	[3H]mazindol (5x10-10 M), [3H]nisoxetine (4x10-9 M)	[3H]GBR12935 (3x10-9 M) 186, [3H]WIN35428 (1x10-8 M) 186	[3H]paroxetine (2x10-10 M), [3H]citalopram (5x10-9 M)
Stoichiometry	1 noradrenaline: 1 Na+:1 Cl- 171	1 dopamine: 1–2 Na+: 1 Cl- 170	1 5-HT:1 Na+:1 Cl- (in), + 1 K+ (out) 197

Comments

[125I]RTI55 labels all three monoamine transporters (NET, DAT and SERT) with affinities between 0.5 and 5 nM. cocaine is an inhibitor of all three transporters with pK_i values between 6.5 and 7.2. Potential alternative splicing sites in non-coding regions of SERT and NET have been identified. A bacterial homologue of SERT shows allosteric modulation by selected anti-depressants 194.

GABA transporter subfamily

Overview

The activity of GABA-transporters located predominantly upon neurones (GAT-1), glia (GAT-3) or both (GAT-2, BGT-1) serves to terminate phasic GABA-ergic transmission, maintain low ambient extracellular concentrations of GABA, and recycle GABA for reuse by neurones. Nonetheless, ambient concentrations of GABA are sufficient to sustain tonic inhibition mediated by high affinity GABA_A receptors in certain neuronal populations 192. GAT1 is the predominant GABA transporter in the brain and occurs primarily upon the terminals of presynaptic neurones and to a much lesser extent upon distal astocytic processes that are in proximity to axons terminals. GAT3 resides predominantly on distal astrocytic terminals that are close to the GABAergic synapse. By contrast, BGT1 occupies an extrasynaptic location possibly along with GAT2 which has limited expression in the brain 181. TauT is a high affinity taurine transporter involved in osmotic balance that occurs in the brain and non-neuronal tissues, such as the kidney, brush border membrane of the intestine and blood brain barrier 156,172. CT1, which transports creatine, has a ubiquitous expression pattern, often co-localizing with creatine kinase 156.

Nomenclature	GAT1	GAT2	GAT3	BGT1	TauT	CT1
Systematic nomenclature	SLC6A1	SLC6A13	SLC6A11	SLC6A12	SLC6A6	SLC6A8
HGNC, UniProt	SLC6A1, P30531	SLC6A13, Q9NSD5	SLC6A11, P48066	SLC6A12, P48065	SLC6A6, P31641	SLC6A8, P48029
Endogenous substrates	GABA	GABA, β-alanine	GABA, β-alanine	GABA, betaine	GABA 145, β-alanine, taurine	creatine
Substrates	nipecotic acid, guvacine	nipecotic acid, guvacine	nipecotic acid, guvacine	–	–	–
Selective inhibitors (pIC50)	SKF89976A (6.9), CI-966 (6.6), NNC-711 (5.9 – 6.9), tiagabine (5.6 – 7.0), LU32-176B (5.4), (R/S) EF-1500 (4.9 – 5.7), (R)-EF-1520 (5.05 – 5.4), (S)-EF-1520 (3.6 – 3.92)	SNAP-5114 (5.2), SNAP-5114 (4.7)	–	NNC052090 (5.6), (R/S) EF-1500 (4.9), (R)-EF-1520 (3.74 – 4.66), (S)-EF-1520 (3.6 – 4.47), LU32-176B (4.0)	–	–
Radioligands (Kd)	[3H]tiagabine	–	–	–	–	–
Stoichiometry	2Na+: 1Cl-: 1GABA	2Na+: 1Cl-:1GABA	≥ 2Na+: 2 Cl-: 1GABA	3Na+: 1 (or 2) Cl-: 1GABA	2Na+: 1Cl-: 1 taurine	Probably 2Na+: 1Cl-: 1 creatine

Comments

The IC₅₀ values for GAT1-4 reported in the table reflect the range reported in the literature from studies of both human and mouse transporters. There is a tendency towards lower IC₅₀ values for the human orthologue 180. SNAP-5114 is only weakly selective for GAT 2 and GAT3, with IC₅₀ values in the range 22 to >30 μM at GAT1 and BGT1, whereas NNC052090 has at least an order of magnitude selectivity for BGT1 [see 157,191 for reviews]. (R)-(1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}pyrrolidin-2-yl)acetic acid is a recently described compound that displays 20-fold selectivity for GAT3 over GAT1 165. In addition to the inhibitors listed, EGYT3886 is a moderately potent, though non-selective, inhibitor of all cloned GABA transporters (IC₅₀ = 26-46 μM; 160). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [3H]GABA into rat synaptosomes have been described 178. Several derivatives of exo-THPO (e.g. N-methyl-exo-THPO and N-acetyloxyethyl-exo-THPO) demonstrate selectivity as blockers of astroglial, versus neuronal, uptake of GABA [see 157,190 for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn²⁺ 158. TauT transports GABA, but with low affinity, but CT1 does not, although it can be engineered to do so by mutagenesis guided by LeuT as a structural template 161. Although inhibitors of creatine transport by CT1 (e.g. β-guanidinopropionic acid, cyclocreatine, guanidinoethane sulfonic acid) are known (e.g. 159) they insufficiently characterized to be included in the table.

Glycine transporter subfamily

Overview

Two gene products, GlyT1 and GlyT2, are known that give rise to transporters that are predominantly located on glia and neurones, respectively. Five variants of GlyT1 (a,b,c,d & e) differing in their N- and C-termini are generated by alternative promoter usage and splicing, and three splice variants of GlyT2 (a,b & c) have also been identified (see 148,163,167,196 for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor-mediated neurotransmission 147,166, but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses 168. Homozygous mice engineered to totally lack GlyT1 exhibit severe respiratory and motor deficiencies due to hyperactive glycinergic signalling and die within the first postnatal day 168,199. Disruption of GlyT1 restricted to forebrain neurones is associated with enhancement of EPSCs mediated by NMDA receptors and behaviours that are suggestive of a promnesic action 207. GlyT2 transporters localised on the axons and boutons of glycinergic neurones appear crucial for efficient transmitter loading of synaptic vesicles but may not be essential for the termination of inhibitory neurotransmission 169,188. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week 169 and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by 173). ATB⁰⁺ (SLCA14) is a transporter for numerous dipolar and cationic amino acids and thus has a much broader substrate specificity than the glycine transporters alongside which it is grouped on the basis of structural similarity 156. ATB⁰⁺ is expressed in various peripheral tissues 156. By contrast PROT (SLC6A7), which is expressed only in brain in association with a subset of excitatory nerve terminals, shows specificity for the transport of L-proline.

Nomenclature	Glycine transporter 1	Glycine transporter 2	ATB0,+	Proline transporter
Systematic nomenclature	SLC6A9	SLC6A5	SLC6A14	SLC6A7
Common abbreviation	GlyT1	GlyT2	ATB0,+	PROT
HGNC, UniProt	SLC6A9, P48067	SLC6A5, Q9Y345	SLC6A14, Q9UN76	SLC6A7, Q99884
Endogenous substrates	glycine, sarcosine	glycine	L-isoleucine > L-leucine, L-methionine > L-phenylalanine > L-tryptophan > L-valine > L-serine 195, β-alanine 144,145	L-proline
Substrates	–	–	1-methyltryptophan 177, BCH, valganciclovir 200, zwitterionic or cationic NOS inhibitors 174	–
Selective inhibitors (pIC50)	(R)-NFPS (8.5 – 9.1), SSR-103800 (8.7), N-methyl-SSR504734 (8.6), LY2365109 (7.8), GSK931145 (7.6)	ALX 1393, ALX 1405, Org 25543 (7.7)	α-methyl-D,L-tryptophan (3.6) 177	LP-403812 (7.0) 208
Radioligands (Kd)	[3H](R)-NPTS (1x10-9 M), [3H]GSK931145 (1.7x10-9 M), [35S]ACPPB (2x10-9 M), [3H]SB-733993 (2.2x10-9 M), [3H]N-methyl-SSR504734 (3.3x10-9 – 8.1x10-9 M), [3H]NFPS (7x10-9 – 2.1x10-8 M)	–	–	–
Stoichiometry	2 Na+: 1 Cl-: 1 glycine	3 Na+: 1 Cl-: 1 glycine	2-3 Na+: 1 Cl-: 1 amino acid 195	Probably 2 Na+: 1 Cl-: 1 L-proline
Comment	–	N-Oleoyl-L-carnitine (0.3μM, 155) and and N-arachidonoylglycine (IC50 5-8 μM, 204) have been described as potential endogenous selective GlyT2 inhibitors	–	–

Comments

sarcosine is a selective transportable inhibitor of GlyT1 and also a weak agonist at the glycine binding site of the NMDA receptor 210, but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) 202. Inhibition of GLYT1 by the sarcosine derivatives NFPS, NPTS and Org 24598 is non-competitive 182,183. IC₅₀ values for Org 24598 reported in the literature vary, most likely due to differences in assay conditions 149,182. The tricyclic antidepressant amoxapine weakly inhibits GlyT2 (IC₅₀ 92 μM) with approximately 10-fold selectivity over GlyT1 184. The endogenous lipids arachidonic acid and anandamide exert opposing effects upon GlyT1a, inhibiting (IC₅₀ ∼ 2 μM) and potentiating (EC₅₀ ∼ 13 μM) transport currents, respectively 185. N-arachidonyl-glycine, N-arachidonyl-γ-aminobutyric acid and N-arachidonyl-D-alanine have been described as endogenous non-competitive inhibitors of GlyT2a, but not GlyT1b 162,175,204. Protons 146 and Zn²⁺ 176 act as non-competitive inhibitors of GlyT1b, with IC₅₀ values of ∼100 nM and ∼10 μM respectively, but neither ion affects GlyT2 (reviewed by 201). Glycine transport by GLYT1 is inhibited by lithium, whereas GLYT2 transport is stimulated (both in the presence of Na⁺) 187.

Neutral amino acid transporter subfamily

Overview

Certain members of neutral amino acid transport family are expressed upon the apical surface of epithelial cells and are important for the absorption of amino acids from the duodenum, jejunum and ileum and their reabsorption within the proximal tubule of the nephron (i.e. B⁰AT1 (SLC6A19), SLC6A17, SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B⁰AT2, SLC6A17) 153.

Nomenclature	B0AT1	B0AT2	B0AT3	NTT5	NTT4	SIT1
Systematic nomenclature	SLC6A19	SLC6A15	SLC6A18	SLC6A16	SLC6A17	SLC6A20
HGNC, UniProt	SLC6A19, Q695T7	SLC6A15, Q9H2J7	SLC6A18, Q96N87	SLC6A16, Q9GZN6	SLC6A17, Q9H1V8	SLC6A20, Q9NP91
Endogenous substrates	L-leucine, L-methionine, L-isoleucine, L-valine > L-asparagine, L-phenylalanine, L-alanine, L-serine > L-threonine, glycine, L-proline 152	L-proline > L-alanine, L-valine, L-methionine, L-leucine > L-isoleucine, L-threonine, L-asparagine, L-serine, L-phenylalanine > glycine 152	L-alanine, glycine > L-methionine, L-phenylalanine, L-leucine, L-histidine, L-glutamine 203	–	L-leucine, L-methionine, L-proline > L-cysteine, L-alanine, L-glutamine, L-serine > L-histidine, glycine 209	L-proline
Stoichiometry	1 Na+: 1 amino acid 154	1 Na+: 1 amino acid 151	Na+- and Cl- -dependent transport 193	–	Na+-dependent, Cl--independent transport 209	2 Na+: 1 Cl-: 1 imino acid 150
Comment	Mutations in B0AT1 are associated with Hartnup disorder	–	–	–	–	–

SLC8 family of sodium/calcium exchangers

Overview

The sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca²⁺-ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA), as well as the sodium/potassium/calcium exchangers (NKCX, SLC24 family), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments.

Nomenclature	Sodium/calcium exchanger 1	Sodium/calcium exchanger 2	Sodium/calcium exchanger 3
Systematic nomenclature	SLC8A1	SLC8A2	SLC8A3
Common abbreviation	NCX1	NCX2	NCX3
HGNC, UniProt	SLC8A1, P32418	SLC8A2, Q9UPR5	SLC8A3, P57103
Stoichiometry	3 Na+ (in): 1 Ca2+ (out) or 4 Na+ (in): 1 Ca2+ (out) 211; Reverse mode 1 Ca2+ (in): 1 Na+ (out)	–	–

Comments

Although subtype-selective inhibitors of NCX function are not widely available, 3,4–dichlorobenzamil and CBDMB act as non-selective NCX inhibitors, while SEA0400, KB-R7943, SN6 and ORM-10103 212 act to inhibit NCX function selectively.

SLC9 family of sodium/hydrogen exchangers

Overview

Sodium/hydrogen exchangers or sodium/proton antiports are a family of transporters that maintain cellular pH by utilising the sodium gradient across the plasma membrane to extrude protons produced by metabolism, in a stoichiometry of 1 Na⁺ (in): 1 H⁺ (out). Several isoforms, NHE6, NHE7, NHE8 and NHE9 appear to locate on intracellular membranes 215–217. Li⁺ and NH₄⁺, but not K⁺, ions may also be transported by some isoforms. Modelling of the topology of these transporters indicates 12 TM regions with an extended intracellular C-terminus containing multiple regulatory sites.

NHE1 is considered to be a ubiquitously-expressed ‘housekeeping’ transporter. NHE3 is highly expressed in the intestine and kidneys and regulate sodium movements in those tissues. NHE10 is present in sperm 220 and osteoclasts 214; gene disruption results in infertile male mice 220.

Nomenclature	Systematic nomenclature	Common abbreviation	HGNC, UniProt
Sodium/hydrogen exchanger 1	SLC9A1	NHE1	SLC9A1, P19634
Sodium/hydrogen exchanger 2	SLC9A2	NHE2	SLC9A2, Q9UBY0
Sodium/hydrogen exchanger 3	SLC9A3	NHE3	SLC9A3, P48764
Sodium/hydrogen exchanger 4	SLC9A4	NHE4	SLC9A4, Q6AI14
Sodium/hydrogen exchanger 5	SLC9A5	NHE5	SLC9A5, Q14940
Sodium/hydrogen exchanger 6	SLC9A6	NHE6	SLC9A6, Q92581
Sodium/hydrogen exchanger 7	SLC9A7	NHE7	SLC9A7, Q96T83
Sodium/hydrogen exchanger 8	SLC9A8	NHE8	SLC9A8, Q9Y2E8
Sodium/hydrogen exchanger 9	SLC9A9	NHE9	SLC9A9, Q8IVB4
solute carrier family 9, subfamily B (NHA1, cation proton antiporter 1), member 1	SLC9B1	NHA1	SLC9B1, Q4ZJI4
solute carrier family 9, subfamily B (NHA2, cation proton antiporter 2), member 2	SLC9B2	NHA2	SLC9B2, Q86UD5
Sodium/hydrogen exchanger 10	SLC9C1	Sperm-NHE	SLC9C1, Q4G0N8
Sodium/hydrogen exchanger 11	SLC9C2	NHE11	SLC9C2, Q5TAH2

Comments

Analogues of the non-selective cation transport inhibitor amiloride appear to inhibit NHE function through competitive inhibition of the extracellular Na⁺ binding site. The more selective amiloride analogues MPA and EIPA exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 213,218,219.

SLC10 family of sodium-bile acid co-transporters

Overview

The SLC10 family transport bile acids, sulphated solutes, and other xenobiotics in a sodium-dependent manner. The founding members, SLC10A1 (NTCP) and SLC10A2 (ASBT) function, along with members of the ABC transporter family (MDR1/ABCB1, BSEP/ABCB11 and MRP2/ABCC2) and the organic solute transporter obligate heterodimer OSTα:OSTβ (SLC51), to maintain the enterohepatic circulation of bile acids 225,234. SLC10A6 (SOAT) functions as a sodium-dependent transporter of sulphated solutes included sulfphated steroids and bile acids 228,230. Transport function has not yet been demonstrated for the 4 remaining members of the SLC10 family, SLC10A3 (P3), SLC10A4 (P4), SLC10A5 (P5), and SLC10A7 (P7), and the identity of their endogenous substrates remain unknown 227,230,231,237. Members of the SLC10 family are predicted to have seven transmembrane domains with an extracellular N-terminus and cytoplasmic C-terminus 221,232.

Nomenclature	Sodium/bile acid and sulphated solute cotransporter 1	Sodium/bile acid and sulphated solute cotransporter 2	Sodium/bile acid and sulphated solute cotransporter 6
Systematic nomenclature	SLC10A1	SLC10A2	SLC10A6
Common abbreviation	NTCP	ASBT	SOAT
HGNC, UniProt	SLC10A1, Q14973	SLC10A2, Q12908	SLC10A6, Q3KNW5
Substrates	tauroursodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid > GCA > cholic acid 235	GDCA > GUDCA, GCDA > taurocholic acid > cholic acid 224	pregnenolone sulphate 228, dehydroepiandrosterone sulphate 230, taurolithocholic acid-3-sulphate, estrone-3-sulphate
Endogenous substrates	T3, dehydroepiandrosterone sulphate 224,227,235, estrone-3-sulphate, iodothyronine sulphates	–	–
Radioligands (Kd)	–	[3H]taurocholic acid 224	–
Stoichiometry	2 Na+: 1 bile acid 221,228	>1 Na+: 1 bile acid 224,238	–
Comment	chenodeoxycholyl-Nε-nitrobenzoxadiazol-lysine is a fluorescent bile acid analogue used as a probe 229.	–	–
Inhibitors (pIC50)	cyclosporin A 226,233, irbesartan 226, propranolol 224	SC-435 (8.82) 222, 264W94 (7.32) 236,239	–

Nomenclature	Sodium/bile acid and sulphated solute cotransporter 3	Sodium/bile acid and sulphated solute cotransporter 4	Sodium/bile acid and sulphated solute cotransporter 5	Sodium/bile acid and sulphated solute cotransporter 7
Systematic nomenclature	SLC10A3	SLC10A4	SLC10A5	SLC10A7
Common abbreviation	P3	P4	P5	P7
HGNC, UniProt	SLC10A3, P09131	SLC10A4, Q96EP9	SLC10A5, Q5PT55	SLC10A7, Q0GE19

Comments

Heterologously expressed SLC10A4 229 or SLC10A7 231 failed to exhibit significant transport of taurocholic acid, pregnenolone sulphate, DHEAS or choline. SLC10A4 has recently been suggested to associate with neuronal vesicles 223.

SLC11 family of proton-coupled metal ion transporters

Overview

The family of proton-coupled metal ion transporters are responsible for movements of divalent cations, particularly ferrous and manganese ions, across the cell membrane (SLC11A2/DMT1) and across endosomal (SLC11A2/DMT1) or lysosomal/phagosomal membranes (SLC11A1/NRAMP1), dependent on proton transport. Both proteins appear to have 12 TM regions and cytoplasmic N- and C- termini. NRAMP1 is involved in antimicrobial action in macrophages, although its precise mechanism is undefined. Facilitated diffusion of divalent cations into phagosomes may increase intravesicular free radicals to damage the pathogen. Alternatively, export of divalent cations from the phagosome may deprive the pathogen of essential enzyme cofactors. SLC11A1/DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells.

Nomenclature	NRAMP1	DMT1
Systematic nomenclature	SLC11A1	SLC11A2
HGNC, UniProt	SLC11A1, P49279	SLC11A2, P49281
Endogenous substrates	Fe2+, Mn2+	Cd2+, Co2+, Cu2+, Fe2+, Mn2+
Stoichiometry	1 H+: 1 Fe2+ (out) or 1 Fe2+ (in): 1 H+ (out)	1 H+: 1 Fe2+ (out) 240

Comments

Loss-of-function mutations in NRAMP1 are associated with increased susceptibility to microbial infection (OMIM: 607948). Loss-of-function mutations in DMT1 are associated with microcytic anemia (OMIM: 206100).

SLC12 family of cation-coupled chloride transporters

Overview

The SLC12 family of chloride transporters contribute to ion fluxes across a variety of tissues, particularly in the kidney and choroid plexus of the brain. Within this family, further subfamilies are identifiable: NKCC1, NKCC2 and NCC constitute a group of therapeutically-relevant transporters, targets for loop and thiazide diuretics. These 12 TM proteins exhibit cytoplasmic termini and an extended extracellular loop at TM7/8 and are kidney-specific (NKCC2 and NCC) or show a more widespread distribution (NKCC1). A second family, the K-Cl co-transporters are also 12 TM domain proteins with cytoplasmic termini, but with an extended extracellular loop at TM 5/6. CCC6 exhibits structural similarities with the K-Cl co-transporters, while CCC9 is divergent, with 11 TM domains and a cytoplasmic N-terminus and extracellular C-terminus.

Nomenclature	Kidney-specific Na-K-Cl symporter	Basolateral Na-K-Cl symporter	Na-Cl symporter
Systematic nomenclature	SLC12A1	SLC12A2	SLC12A3
Common abbreviation	NKCC2	NKCC1	NCC
HGNC, UniProt	SLC12A1, Q13621	SLC12A2, P55011	SLC12A3, P55017
Inhibitors (pIC50)	bumetanide 242, furosemide 242, piretanide 242	bumetanide 242, furosemide 242, piretanide 242	chlorothiazide, hydrochlorothiazide, metolazone
Stoichiometry	1 Na+: 1 K+: 2 Cl- (in)	1 Na+: 1 K+: 2 Cl- (in)	1 Na+: 1 Cl- (in)

Nomenclature	K-Cl cotransporter 1	K-Cl cotransporter 2	K-Cl cotransporter 3	K-Cl cotransporter 4
Systematic nomenclature	SLC12A4	SLC12A5	SLC12A6	SLC12A7
Common abbreviation	KCC1	KCC2	KCC3	KCC4
HGNC, UniProt	SLC12A4, Q9UP95	SLC12A5, Q9H2X9	SLC12A6, Q9UHW9	SLC12A7, Q9Y666
Inhibitors (pIC50)	DIOA	DIOA, VU0240551 241	DIOA	DIOA
Stoichiometry	1 K+: 1 Cl- (out)	1 K+: 1 Cl- (out)	1 K+: 1 Cl- (out)	1 K+: 1 Cl- (out)

Nomenclature	Cation-chloride cotransporter 9	Cation-chloride cotransporter 6
Systematic nomenclature	SLC12A8	SLC12A9
Common abbreviation	CCC9	CCC6
HGNC, UniProt	SLC12A8, A0AV02	SLC12A9, Q9BXP2
Substrates	spermine, L-glutamic acid, spermidine, L-aspartic acid	–
Stoichiometry	Unknown	–
Comment	–	CCC6 is regarded as an orphan transporter

Comments

DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR 243.

SLC13 family of sodium-dependent sulphate/carboxylate transporters

Overview

Within the SLC13 family, two groups of transporters may be differentiated on the basis of the substrates transported: NaS1 and NaS2 convey sulphate, while NaC1-3 transport carboxylates. NaS1 and NaS2 transporters are made up of 13 TM domains, with an intracellular N terminus and are electrogenic with physiological roles in the intestine, kidney and placenta. NaC1, NaC2 and NaC3 are made up of 11 TM domains with an intracellular N terminus and are electrogenic, with physiological roles in the kidney and liver.

Nomenclature	Na+/sulfate cotransporter	Na+/dicarboxylate cotransporter 1	Na+/dicarboxylate cotransporter 3	Na+/sulfate cotransporter	Na+/citrate cotransporter
Systematic nomenclature	SLC13A1	SLC13A2	SLC13A3	SLC13A4	SLC13A5
Common abbreviation	NaS1	NaC1	NaC3	NaS2	NaC2
HGNC, UniProt	SLC13A1, Q9BZW2	SLC13A2, Q13183	SLC13A3, Q8WWT9	SLC13A4, Q9UKG4	SLC13A5, Q86YT5
Endogenous substrates	SeO42-, S2O32-, SO42-	citric acid, succinic acid	citric acid, succinic acid	SO42-	citric acid, pyruvic acid
Stoichiometry	3 Na+: 1 SO42- (in)	3 Na+: 1 dicarboxylate2- (in)	Unknown	3 Na+: SO42- (in)	Unknown

SLC14 family of facilitative urea transporters

Overview

As a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing urea movement down its concentration gradient. Multiple splice variants of these transporters have been identified; for UT-A transporters, in particular, there is evidence for cell-specific expression of these variants with functional impact 245. Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM domains, with a glycosylated extracellular loop at TM5/6, and intracellular C- and N-termini. The UT-A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT-A2 and UT-A3 splice variants.

Nomenclature	Erythrocyte urea transporter	Kidney urea transporter
Systematic nomenclature	SLC14A1	SLC14A2
Common abbreviation	UT-B	UT-A
HGNC, UniProt	SLC14A1, Q13336	SLC14A2, Q15849
Endogenous substrates	ammonium carbonate 246, urea 246, formamide 246	urea 244
Substrates	acrylamide 246, acetamide 246, methylurea 246	–
Stoichiometry	Equilibrative	Equilibrative

SLC15 family of peptide transporters

Overview

The SLC15 family of peptide transporters may be divided on the basis of structural and functional differences into two subfamilies: SLC15A1 (PepT1) and SLC15A2 (PepT2) transport di- and tripeptides, but not amino acids, whereas SLC15A3 (PHT2) and SLC15A4 (PHT1) transport L-histidine and some di- and tripeptides 251. The transporters are 12 TM proteins with intracellular termini and an extended extracellular loop at TM 9/10. The crystal structure of PepTSo (a prokaryote homologue of PepT1 and PepT2 from Shewanella oneidensis) confirms many of the predicted structural features of mammalian PepT1 and PepT2 261.

PHT1 has been suggested to be intracellular 262, while PHT2 protein is located on lysosomes in transfected cells 250,257,264. PHT1 is hypothesised to mediate efflux of bacterial-derived peptides into the cytosol perhaps in the colon where SLC15A4 mRNA expression is increased in inflammatory bowel disease 259. Transport via PHT1 may be important in immune responses as both Toll-like receptor- and NOD1-mediated responses are reduced in PHT1 knockout mice or mouse strains expressing mutations in PHT1 249,265.

Nomenclature	Peptide transporter 1	Peptide transporter 2	Peptide transporter 3	Peptide transporter 4
Systematic nomenclature	SLC15A1	SLC15A2	SLC15A3	SLC15A4
Common abbreviation	PepT1	PepT2	PHT2	PHT1
HGNC, UniProt	SLC15A1, P46059	SLC15A2, Q16348	SLC15A3, Q8IY34	SLC15A4, Q8N697
Endogenous substrates	5-aminolevulinic acid 253, dipeptides 253, tripeptides 253	5-aminolevulinic acid, dipeptides, tripeptides	L-histidine, carnosine, dipeptides, tripeptides	L-histidine, carnosine, dipeptides, tripeptides
Substrates	fMet-Leu-Phe 260, cyclacillin 254, valacyclovir 255, cefadroxil 254, muramyl dipeptide 268	cyclacillin 254, cefadroxil 254	–	valacyclovir 247
Inhibitors (pIC50)	4-AMBA 252, Lys[Z(NO2)]-Pro 258	Lys[Z(NO2)]-Lys[Z(NO2)] 248,267, Lys[Z(NO2)]-Pro	–	–
Radioligands (Kd)	[11C]GlySar, [14C]GlySar, [3H]GlySar	[11C]GlySar, [14C]GlySar, [3H]GlySar	[14C]histidine, [3H]histidine	[14C]histidine, [3H]histidine
Stoichiometry	1 H+: 1 zwitterionic peptide (in)	2 H+: 1 zwitterionic peptide (in)	Unknown	Unknown

Comments

The PepT1 and PepT2 transporters are particularly promiscuous in the transport of dipeptides and tripeptides from the endogenous amino acids, as well as some D-amino acid containing peptides. PepT1 has also been exploited to allow delivery of therapeutic pro-drugs, such as those for zidovudine 256, sulpiride 269 and cytarabine 266.

D-Ala-Lys-AMCA has been used as a fluorescent probe to identify transport via both PepT1 and PepT2 263.

SLC16 family of monocarboxylate transporters

Overview

Members of the SLC16 family may be divided into subfamilies on the basis of substrate selectivities, particularly lactate (e.g. L-lactic acid), pyruvic acid and ketone bodies, as well as aromatic amino acids. Topology modelling suggests 12 TM domains, with intracellular termini and an extended loop at TM 6/7.

The proton-coupled monocarboxylate transporters (monocarboxylate transporters 1, 4, 2 and 3) allow transport of the products of cellular metabolism, principally lactate (e.g. L-lactic acid) and pyruvic acid.

Nomenclature	Monocarboxylate transporter 1	Monocarboxylate transporter 4	Monocarboxylate transporter 2	Monocarboxylate transporter 3
Systematic nomenclature	SLC16A1	SLC16A3	SLC16A7	SLC16A8
Common abbreviation	MCT1	MCT4	MCT2	MCT3
HGNC, UniProt	SLC16A1, P53985	SLC16A3, O15427	SLC16A7, O60669	SLC16A8, O95907
Endogenous substrates	β-D-hydroxybutyric acid, L-lactic acid, pyruvic acid	L-lactic acid, pyruvic acid	L-lactic acid, pyruvic acid	L-lactic acid
Substrates	γ-hydroxybutyric acid 272	–	–	–
Stoichiometry	1 H+: 1 monocarboxylate- (out)	1 H+: 1 monocarboxylate- (out)	1 H+: 1 monocarboxylate- (out)	1 H+: 1 monocarboxylate- (out)

Nomenclature	Monocarboxylate transporter 8	Monocarboxylate transporter 10
Systematic nomenclature	SLC16A2	SLC16A10
Common abbreviation	MCT8	TAT1
HGNC, UniProt	SLC16A2, P36021	SLC16A10, Q8TF71
Endogenous substrates	T3 270, T4 270	L-tryptophan, L-phenylalanine, L-DOPA, L-tyrosine
Stoichiometry	Unknown	Unknown

Nomenclature	Monocarboxylate transporter 5	Monocarboxylate transporter 6	Monocarboxylate transporter 7	Monocarboxylate transporter 9	Monocarboxylate transporter 11	Monocarboxylate transporter 12	Monocarboxylate transporter 13	Monocarboxylate transporter 14
Systematic nomenclature	SLC16A4	SLC16A5	SLC16A6	SLC16A9	SLC16A11	SLC16A12	SLC16A13	SLC16A14
Common abbreviation	MCT5	MCT6	MCT7	MCT9	MCT11	MCT12	MCT13	MCT14
HGNC, UniProt	SLC16A4, O15374	SLC16A5, O15375	SLC16A6, O15403	SLC16A9, Q7RTY1	SLC16A11, Q8NCK7	SLC16A12, Q6ZSM3	SLC16A13, Q7RTY0	SLC16A14, Q7RTX9
Stoichiometry	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
Comment	–	MCT6 has been reported to transport bumetanide, but not short chain fatty acids 271	–	–	–	–	–	–

Comments

MCT1 and MCT2, but not MCT3 and MCT4, are inhibited by CHC, which also inhibits members of the mitochondrial transporter family, SLC25.

MCT5-MCT7, MCT9 and MCT11-14 are regarded as orphan transporters.

SLC17 phosphate and organic anion transporter family

Overview

The SLC17 family are sometimes referred to as Type I sodium-phosphate co-transporters, alongside Type II (SLC34 family) and Type III (SLC20 family) transporters. Within the SLC17 family, however, further subgroups of organic anion transporters may be defined, allowing the accumulation of sialic acid in the endoplasmic reticulum and glutamate (e.g. L-glutamic acid) or nucleotides in synaptic and secretory vesicles. Topology modelling suggests 12 TM domains.

Type I sodium-phosphate co-transporters

Overview

Type I sodium-phosphate co-transporters are expressed in the kidney and intestine.

Nomenclature	Sodium/phosphate cotransporter 1	Sodium/phosphate cotransporter 3	Sodium/phosphate cotransporter 4	Sodium/phosphate cotransporter homolog
Systematic nomenclature	SLC17A1	SLC17A2	SLC17A3	SLC17A4
Common abbreviation	NPT1	NPT3	NPT4	–
HGNC, UniProt	SLC17A1, Q14916	SLC17A2, O00624	SLC17A3, O00476	SLC17A4, Q9Y2C5
Substrates	Cl- 275, probenecid 274, PO34- 275, uric acid 275, penicillin G 274, organic acids 275	–	–	–
Stoichiometry	Unknown	Unknown	Unknown	Unknown

Sialic acid transporter

Overview

The sialic acid transporter is expressed on both lysosomes and synaptic vesicles, where it appears to allow export of sialic acid and accumulation of acidic amino acids, respectively 277, driven by proton gradients. In lysosomes, degradation of glycoproteins generates amino acids and sugar residues, which are metabolized further following export from the lysosome.

Nomenclature	Sialin
Systematic nomenclature	SLC17A5
Common abbreviation	AST
HGNC, UniProt	SLC17A5, Q9NRA2
Endogenous substrates	L-glutamic acid (in) 277, L-lactic acid, L-aspartic acid 277, gluconate (out), sialic acid, glucuronic acid
Stoichiometry	1 H+: 1 sialic acid (out)

Comments

Loss-of-function mutations in sialin are associated with Salla disease (OMIM: 604369), an autosomal recessive neurodegenerative disorder associated with sialic acid storage disease 279.

Vesicular glutamate transporters (VGLUTs)

Overview

Vesicular glutamate transporters (VGLUTs) allow accumulation of glutamate into synaptic vesicles, as well as secretory vesicles in endocrine tissues. The roles of VGLUTs in kidney and liver are unclear. These transporters appear to utilize the proton gradient and also express a chloride conductance 273.

Nomenclature	Vesicular glutamate transporter 1	Vesicular glutamate transporter 2	Vesicular glutamate transporter 3
Systematic nomenclature	SLC17A7	SLC17A6	SLC17A8
Common abbreviation	VGLUT1	VGLUT2	VGLUT3
HGNC, UniProt	SLC17A7, Q9P2U7	SLC17A6, Q9P2U8	SLC17A8, Q8NDX2
Endogenous substrates	L-glutamic acid > D-glutamic acid	L-glutamic acid > D-glutamic acid	L-glutamic acid > D-glutamic acid
Stoichiometry	Unknown	Unknown	Unknown

Comments

Endogenous ketoacids produced during fasting have been proposed to regulate VGLUT function through blocking chloride ion-mediated allosteric enhancement of transporter function 276.

Vesicular nucleotide transporter

Overview

The vesicular nucleotide transporter is the most recent member of the SLC17 family to have an assigned function. Uptake of ATP was independent of pH, but dependent on chloride ions and membrane potential 278.

Nomenclature	Vesicular nucleotide transporter
Systematic nomenclature	SLC17A9
Common abbreviation	VNUT
HGNC, UniProt	SLC17A9, Q9BYT1
Endogenous substrates	ATP 278, GTP 278, GDP 278
Stoichiometry	Unknown

Comments

VGLUTs and VNUT can be inhibited by DIDS and evans blue dye.

SLC18 family of vesicular amine transporters

Overview

The vesicular amine transporters (VATs) are putative 12 TM domain proteins that function to transport singly positively charged amine neurotransmitters and hormones from the cytoplasm and concentrate them within secretory vesicles. They function as amine/proton antiporters driven by secondary active transport utilizing the proton gradient established by a multi-subunit vacuolar ATPase that acidifies secretory vesicles (reviewed by 283). The vesicular acetylcholine transporter (VAChT; 287) localizes to cholinergic neurons, but non-neuronal expression has also been claimed 290. Vesicular monoamine transporter 1 (VMAT1, 285) is mainly expressed in peripheral neuroendocrine cells, but most likely not in the CNS, whereas VMAT2 286 distributes between both central and peripheral sympathetic monoaminergic neurones 284.

Nomenclature	Vesicular monoamine transporter 1	Vesicular monoamine transporter 2	Vesicular acetylcholine transporter	solute carrier family 18, subfamily B, member 1
Systematic nomenclature	SLC18A1	SLC18A2	SLC18A3	SLC18B1
Common abbreviation	VMAT1	VMAT2	VAChT	–
HGNC, UniProt	SLC18A1, P54219	SLC18A2, Q05940	SLC18A3, Q16572	SLC18B1, Q6NT16
Endogenous substrates	5-HT (Ki 1.4x10-6 M) 286, (-)-adrenaline (Ki 5.5x10-6 M) 286, (-)-noradrenaline (Ki 1.37x10-5 M) 286, dopamine (Ki 3.8x10-6 M) 286, histamine (Ki 4.696x10-3 M) 286	5-HT (Ki 9x10-7 M) 286, (-)-adrenaline (Ki 1.9x10-6 M) 286, (-)-noradrenaline (Ki 3.4x10-6 M) 286, dopamine (Ki 1.4x10-6 M) 286, histamine (Ki 1.43x10-4 M) 286	acetylcholine (Ki 7.94x10-4 M) 280,288, choline (Ki 5x10-4 M) 280,288	–
Substrates	β-phenylethylamine (Ki 3.4x10-5 M) 286, dextroamphetamine (Ki 4.7x10-5 M) 286, MPP+ (Ki 6.9x10-5 M) 286, MDMA (Ki 1.9x10-5 M) 286, fenfluramine (Ki 3.1x10-6 M) 286	β-phenylethylamine (Ki 3.7x10-6 M) 286, dextroamphetamine (Ki 2.1x10-6 M) 286, MPP+ (Ki 8.9x10-6 M) 286, MDMA (Ki 6.9x10-6 M) 286, fenfluramine (Ki 5.1x10-6 M) 286	TPP+ 281, ethidium 281, N-methyl-pyridinium-2-aldoxime 281, N-(4′-pentanonyl)-4-(4″-dimethylamino-styryl)pyridinium 281	–
Inhibitors (pIC50)	reserpine (pKi 7.45) 286, ketanserin (pKi 5.8) 286, tetrabenazine (pKi 4.7) 286	reserpine (pKi 7.9) 286, tetrabenazine (pKi 7.0) 286, ketanserin (pKi 6.3) 286	aminobenzovesamicol (pKi 10.9) 282, vesamicol (pKi 8.7) 282	–
Radioligands (Kd)	–	[11C]DTBZ, [125I]8-azido-3-iodoketanserine, [3H]TBZOH (6.6x10-9 M) 291, [125I]iodovinyl-TBZ (8.2x10-9 M) 289	[123I]iodobenzovesamicol, [3H]vesamicol (4.1x10-9 M) 291	–
Stoichiometry	1 amine (in): 2H+ (out)	1 amine (in): 2H+ (out)	1 amine (in): 2H+ (out)	–

Comments

pK_i values for endogenous and synthetic substrate inhibitors of human VMAT1 and VMAT2 are for inhibition of [3H]5-HT uptake in transfected and permeabilised CV-1 cells as detailed by 286. In addition to the monoamines listed in the table, the trace amines tyramine and β-phenylethylamine are probable substrates for VMAT2 284. Probes listed in the table are those currently employed; additional agents have been synthesized (e.g. 292).

SLC19 family of vitamin transporters

Overview

The B vitamins folic acid and thiamine are transported across the cell membrane, particularly in the intestine, kidneys and placenta, using pH differences as driving forces. Topological modelling suggests the transporters have 12 TM domains.

Nomenclature	Reduced folate transporter 1	Thiamine transporter 1	Thiamine transporter 2
Systematic nomenclature	SLC19A1	SLC19A2	SLC19A3
Common abbreviation	FOLT	ThTr1	ThTr2
HGNC, UniProt	SLC19A1, P41440	SLC19A2, O60779	SLC19A3, Q9BZV2
Endogenous substrates	thiamine monophosphate 298, tetrahydrofolic acid 296, N5-methylfolate 296, Organic phosphates; in particular, adenine nucleotides, Other tetrahydrofolate-cofactors	thiamine	thiamine
Substrates	folic acid 296, methotrexate, folinic acid, N5-formyltetrahydrofolate	–	–
Radioligands (Kd)	[3H]folic acid 293, [3H]methotrexate 293	[3H]thiamine 295	[3H]thiamine 297
Stoichiometry	Folate (in): organic phosphate (out), precise stoichiometry unknown	A facilitative carrier not known to be coupled to an inorganic or organic ion gradient	A facilitative carrier not known to be coupled to an inorganic or organic ion gradient

Comments

Loss-of-function mutations in ThTr1 underlie thiamine-responsive megaloblastic anemia syndrome 294.

SLC20 family of sodium-dependent phosphate transporters

Overview

The SLC20 family is looked upon not only as ion transporters, but also as retroviral receptors. As ion transporters, they are sometimes referred to as Type III sodium-phosphate co-transporters, alongside Type I (SLC17 family) and Type II (SLC34 family). PiTs are cell-surface transporters, composed of ten TM domains with extracellular C- and N-termini. PiT1 is a focus for dietary PO34- and vitamin D regulation of parathyroid hormone secretion from the parathyroid gland. PiT2 appears to be involved in intestinal absorption of dietary PO34-.

Nomenclature	Sodium-dependent phosphate transporter 1	Sodium-dependent phosphate transporter 2
Systematic nomenclature	SLC20A1	SLC20A2
Common abbreviation	PiT1	PiT2
HGNC, UniProt	SLC20A1, Q8WUM9	SLC20A2, Q08357
Substrates	AsO43− 299, PO34- 299	PO34- 299
Stoichiometry	>1 Na+: 1 HPO42- (in)	>1 Na+: 1 HPO42- (in)

SLC22 family of organic cation and anion transporters

Overview

The SLC22 family of transporters is mostly composed of non-selective transporters, which are expressed highly in liver, kidney and intestine, playing a major role in drug disposition. The family may be divided into three subfamilies based on the nature of the substrate transported: organic cations (OCTs), organic anions (OATs) and organic zwiterrion/cations (OCTN). Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2.

Organic cation transporters (OCT)

Overview

Organic cation transporters (OCT) are electrogenic, Na⁺-independent and reversible.

Nomenclature	Organic cation transporter 1	Organic cation transporter 2	Organic cation transporter 3
Systematic nomenclature	SLC22A1	SLC22A2	SLC22A3
Common abbreviation	OCT1	OCT2	OCT3
HGNC, UniProt	SLC22A1, O15245	SLC22A2, O15244	SLC22A3, O75751
Endogenous substrates	5-HT, PGE2, PGF2α, choline	dopamine 303, histamine 303, PGE2 304	5-HT 307, (-)-noradrenaline 307, dopamine 307
Substrates	tetraethylammonium, desipramine, MPP+, metformin, acyclovir	(+)-tubocurarine 302, tetraethylammonium 302, pancuronium 302, MPP+ 302	quinidine, tetraethylammonium, MPP+
Stoichiometry	Unknown	Unknown	Unknown

Comments

corticosterone and quinine are able to inhibit all three organic cation transporters.

Organic zwitterions/cation transporters (OCTN)

Overview

Organic zwitterions/cation transporters (OCTN) function as organic cation uniporters, organic cation/proton exchangers or sodium/L-carnitine co-transporters.

Nomenclature	Organic cation/carnitine transporter 1	Organic cation/carnitine transporter 2	Carnitine transporter 2
Systematic nomenclature	SLC22A4	SLC22A5	SLC22A16
Common abbreviation	OCTN1	OCTN2	CT2
HGNC, UniProt	SLC22A4, Q9H015	SLC22A5, O76082	SLC22A16, Q86VW1
Endogenous substrates	L-carnitine	acetyl-L-carnitine, L-carnitine	L-carnitine
Substrates	pyrilamine, tetraethylammonium, verapamil, MPP+	pyrilamine, tetraethylammonium, verapamil, MPP+	–
Stoichiometry	Unknown	Unknown	Unknown

Organic anion transporters (OATs)

Overview

Organic anion transporters (OATs) are non-selective transporters prominent in the kidney and intestine.

Nomenclature	Organic anion transporter 1	Organic anion transporter 2	Organic anion transporter 3	Organic anion transporter 7	Organic anion transporter 5	Organic anion transporter 4
Systematic nomenclature	SLC22A6	SLC22A7	SLC22A8	SLC22A9	SLC22A10	SLC22A11
Common abbreviation	OAT1	OAT2	OAT3	OAT4	OAT5	–
HGNC, UniProt	SLC22A6, Q4U2R8	SLC22A7, Q9Y694	SLC22A8, Q8TCC7	SLC22A9, Q8IVM8	SLC22A10, Q63ZE4	SLC22A11, Q9NSA0
Substrates	aminohippuric acid, non-steroidal anti-inflammatory drugs	PGE2, aminohippuric acid, non-steroidal anti-inflammatory drugs	cimetidine 305, ochratoxin A 305, estrone-3-sulphate 305, aminohippuric acid 305	–	ochratoxin A 306	dehydroepiandrosterone sulphate 300, ochratoxin A 300, estrone-3-sulphate 300
Stoichiometry	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown

Urate transporter

Nomenclature	Urate anion exchanger 1
Systematic nomenclature	SLC22A12
Common abbreviation	URAT1
HGNC, UniProt	SLC22A12, Q96S37
Endogenous substrates	orotic acid 301, uric acid 301
Stoichiometry	Unknown

Orphan or poorly characterized SLC22 family members

Nomenclature	Systematic nomenclature	Common abbreviation	HGNC, UniProt
Organic cation transporter-like 3	SLC22A13	ORCTL3	SLC22A13, Q9Y226
Organic cation transporter-like 4	SLC22A14	ORCTL4	SLC22A14, Q9Y267
Fly-like putative transporter 1	SLC22A15	FLIPT1	SLC22A15, Q8IZD6
Brain-type organic cation transporter	SLC22A17	BOIT	SLC22A17, Q8WUG5
Organic cation transporter-like 2	SLC22A18	ORCTL2	SLC22A18, Q96BI1
OAT6	SLC22A20	–	SLC22A20, A6NK97
–	SLC22A23	–	SLC22A23, A1A5C7
–	SLC22A24	–	SLC22A24, Q8N4F4
UST6	SLC22A25	–	SLC22A25, Q6T423
solute carrier family 22, member 31	SLC22A31	–	SLC22A31, A6NKX4

SLC23 family of ascorbic acid transporters

Overview

Predicted to be 12 TM segment proteins, members of this family transport the reduced form of ascorbic acid (while the oxidized form may be handled by members of the SLC2 family (GLUT1/SLC2A1, GLUT3/SLC2A3 and GLUT4/SLC2A4). phloretin is considered a non-selective inhibitor of these transporters, with an affinity in the micromolar range.

Nomenclature	Sodium-dependent vitamin C transporter 1	Sodium-dependent vitamin C transporter 2	Sodium-dependent vitamin C transporter 3	Sodium-dependent nucleobase transporter
Systematic nomenclature	SLC23A1	SLC23A2	SLC23A3	SLC23A4
Common abbreviation	SVCT1	SVCT2	SVCT3	SNBT1
HGNC, UniProt	SLC23A1, Q9UHI7	SLC23A2, Q9UGH3	SLC23A3, Q6PIS1	SLC23A4P, –
Endogenous substrates	L-ascorbic acid > D-ascorbic acid > dehydroascorbic acid 308	L-ascorbic acid > D-ascorbic acid > dehydroascorbic acid 308	–	uracil > thymine > guanine, hypoxanthine > xanthine, uridine 309
Substrates	–	–	–	–
Inhibitors (pIC50)	phloretin 308	–	–	5-fluorouracil 309
Radioligands (Kd)	[14C]ascorbic acid	[14C]ascorbic acid	–	–
Stoichiometry	2 Na+: 1 ascorbic acid (in) 308	2 Na+: 1 ascorbic acid (in) 308	–	1 Na+: 1 uracil (in) 309
Comment	–	–	SLC23A3 does not transport ascorbic acid and remains an orphan transporter.	SLC23A4/SNBT1 is found in rodents and non-human primates, but the sequence is truncated in the human genome and named as a pseudogene, SLC23A4P

SLC24 family of sodium/potassium/calcium exchangers

Overview

The sodium/potassium/calcium exchange family of transporters utilize the extracellular sodium gradient to drive calcium and potassium co-transport out of the cell. As is the case for NCX transporters (SLC8A family), NKCX transporters are thought to be bidirectional, with the possibility of calcium influx following depolarization of the plasma membrane. Topological modeling suggests the presence of 10 TM domains, with a large intracellular loop between the fifth and sixth TM regions.

Nomenclature	Sodium/potassium/calcium exchanger 1	Sodium/potassium/calcium exchanger 2	Sodium/potassium/calcium exchanger 3	Sodium/potassium/calcium exchanger 4	Sodium/potassium/calcium exchanger 5	Sodium/potassium/calcium exchanger 6
Systematic nomenclature	SLC24A1	SLC24A2	SLC24A3	SLC24A4	SLC24A5	SLC24A6
Common abbreviation	NKCX1	NKCX2	NKCX3	NKCX4	NKCX5	NKCX6
HGNC, UniProt	SLC24A1, O60721	SLC24A2, Q9UI40	SLC24A3, Q9HC58	SLC24A4, Q8NFF2	SLC24A5, Q71RS6	SLC8B1, Q6J4K2
Stoichiometry	4Na+:(1Ca2+ + 1K+)	–	–	–	–	–

Comments

NKCX6 exhibits sufficient structural diversity for its function as a NKCX to be questioned 310.

To date, there are no agents selective for this family of transporters.

SLC25 family of mitochondrial transporters

Overview

Mitochondrial transporters are nuclear-encoded proteins, which convey solutes across the inner mitochondrial membrane. Topological modelling suggests homodimeric transporters, each with six TM segments and termini in the cytosol.

Mitochondrial di- and tri-carboxylic acid transporter subfamily

Overview

Mitochondrial di- and tri-carboxylic acid transporters are grouped on the basis of commonality of substrates and include the citrate transporter which facilitates citric acid export from the mitochondria to allow the generation of oxalacetic acid and acetyl CoA through the action of ATP:citrate lyase.

Nomenclature	Mitochondrial citrate transporter	Mitochondrial dicarboxylate transporter	Mitochondrial oxoglutarate carrier	Mitochondrial oxodicarboxylate carrier	–	–
Systematic nomenclature	SLC25A1	SLC25A10	SLC25A11	SLC25A21	SLC25A34	SLC25A35
Common abbreviation	CIC	DIC	OGC	ODC	–	–
HGNC, UniProt	SLC25A1, P53007	SLC25A10, Q9UBX3	SLC25A11, Q02978	SLC25A21, Q9BQT8	SLC25A34, Q6PIV7	SLC25A35, Q3KQZ1
Substrates	citric acid, malic acid, PEP	malic acid, succinic acid, PO34-, S2O32-, SO42-	malic acid, α-ketoglutaric acid	α-ketoglutaric acid, α-oxoadipic acid	–	–
Inhibitors (pIC50)	1,2,3-benzenetricarboxylic acid	–	–	–	–	–
Stoichiometry	Malate2- (in): H-citrate2- (out)	PO34- (in): malate2- (out)	Malate2- (in): oxoglutarate2- (out)	Oxoadipate (in): oxoglutarate (out)	–	–

Mitochondrial amino acid transporter subfamily

Overview

Mitochondrial amino acid transporters can be subdivided on the basis of their substrates. Mitochondrial ornithine transporters play a role in the urea cycle by exchanging cytosolic ornithine (L-ornithine and D-ornithine) for mitochondrial citrulline (L-citrulline and D-citrulline) in equimolar amounts. Further members of the family include transporters of S-adenosylmethionine and carnitine.

Nomenclature	Mitochondrial glutamate carrier 1	Mitochondrial glutamate carrier 2	AGC1	AGC2
Systematic nomenclature	SLC25A22	SLC25A18	SLC25A12	SLC25A13
Common abbreviation	GC1	GC2	AGC1	AGC2
HGNC, UniProt	SLC25A22, Q9H936	SLC25A18, Q9H1K4	SLC25A12, O75746	SLC25A13, Q9UJS0
Substrates	L-glutamic acid	L-glutamic acid	L-glutamic acid, L-aspartic acid, 2-amino-3-sulfinopropanoic acid	L-glutamic acid, L-aspartic acid, 2-amino-3-sulfinopropanoic acid
Stoichiometry	Glutamate: H+ (bidirectional)	Glutamate: H+ (bidirectional)	Aspartate: glutamate H+ (bidirectional)	Aspartate: glutamate H+ (bidirectional)

Nomenclature	Mitochondrial ornithine transporter 1	Mitochondrial ornithine transporter 2	Carnitine/acylcarnitine carrier
Systematic nomenclature	SLC25A15	SLC25A2	SLC25A20
Common abbreviation	ORC1	ORC2	CAC
HGNC, UniProt	SLC25A15, Q9Y619	SLC25A2, Q9BXI2	SLC25A20, O43772
Substrates	L-arginine 311, L-citrulline 311, L-lysine 311, L-ornithine 311	L-arginine 311, L-citrulline 311, L-lysine 311, L-ornithine 311, L-histidine 311, D-histidine 311, D-arginine 311, D-lysine 311, D-ornithine 311, D-citrulline 311	–
Stoichiometry	1 Ornithine (in) :1 citrulline: 1 H+ (out)	1 Ornithine (in) :1 citrulline: 1 H+ (out)	–
Comment	–	–	Exchanges cytosolic acylcarnitine for mitochondrial carnitine

Nomenclature	solute carrier family 25, member 47	solute carrier family 25, member 48	ORNT3	–	CGI-69	MCFP	–	–
Systematic nomenclature	SLC25A47	SLC25A48	SLC25A29	SLC25A38	SLC25A39	SLC25A40	SLC25A44	SLC25A45
Common abbreviation	–	–	ORNT3	–	–	–	–	–
HGNC, UniProt	SLC25A47, Q6Q0C1	SLC25A48, Q6ZT89	SLC25A29, Q8N8R3	SLC25A38, Q96DW6	SLC25A39, Q9BZJ4	SLC25A40, Q8TBP6	SLC25A44, Q96H78	SLC25A45, Q8N413

Comments

Both ornithine transporters are inhibited by the polyamine spermine 312. Loss-of-function mutations in these genes are associated with hyperornithinemia-hyperammonemia-homocitrullinuria.

Mitochondrial phosphate transporters

Overview

Mitochondrial phosphate transporters allow the import of inorganic PO34- for ATP production.

Nomenclature	Mitochondrial phosphate carrier
Systematic nomenclature	SLC25A3
Common abbreviation	PHC
HGNC, UniProt	SLC25A3, Q00325
Stoichiometry	PO34- (in): OH- (out) or PO34-: H+ (in)

Mitochondrial nucleotide transporter subfamily

Overview

Mitochondrial nucleotide transporters, defined by structural similarlities, include the adenine nucleotide translocator family (SLC25A4, SLC25A5, SLC25A6 and SLC25A31), which under conditions of aerobic metabolism, allow coupling between mitochondrial oxidative phosphorylation and cytosolic energy consumption by exchanging cytosolic ADP for mitochondrial ATP. Further members of the mitochondrial nucleotide transporter subfamily convey diverse substrates including CoA, although not all members have had substrates identified.

Nomenclature	Mitochondrial adenine nucleotide translocator 1	Mitochondrial adenine nucleotide translocator 2	Mitochondrial adenine nucleotide translocator 3	Mitochondrial adenine nucleotide translocator 4	–
Systematic nomenclature	SLC25A4	SLC25A5	SLC25A6	SLC25A31	SLC25A42
Common abbreviation	ANT1	ANT2	ANT3	ANT4	–
HGNC, UniProt	SLC25A4, P12235	SLC25A5, P05141	SLC25A6, P12236	SLC25A31, Q9H0C2	SLC25A42, Q86VD7
Inhibitors (pIC50)	BKA, CATR	–	–	–	–
Stoichiometry	ADP3- (in): ATP4- (out)	ADP3- (in): ATP4- (out)	ADP3- (in): ATP4- (out)	ADP3- (in): ATP4- (out)	–
Substrates	–	–	–	–	ADP

Nomenclature	Graves disease carrier	Peroxisomal membrane protein	Deoxynucleotide carrier 1	S-Adenosylmethionine carrier
Systematic nomenclature	SLC25A16	SLC25A17	SLC25A19	SLC25A26
Common abbreviation	GDC	PMP34	DNC	SAMC1
HGNC, UniProt	SLC25A16, P16260	SLC25A17, O43808	SLC25A19, Q9HC21	SLC25A26, Q70HW3
Substrates	CoA and congeners	ADP, ATP, AMP	Deoxynucleotide Diphosphates (dNDPs), Deoxynucleotide Triphosphates (dNTPs), Dideoxynucleotide Triphosphates (ddNTPs), Nucleotide Diphosphates (NDPs)	S-adenosyl methionine
Stoichiometry	CoA (in)	ATP (in)	dNDP (in): ATP (out)	–

Nomenclature	Mitochondrial phosphate carrier 1	Mitochondrial phosphate carrier 2	Mitochondrial phosphate carrier 3	MFT	PNC1	–	SCaMC-3L	–
Systematic nomenclature	SLC25A24	SLC25A23	SLC25A25	SLC25A32	SLC25A33	SLC25A36	SLC25A41	SLC25A43
Common abbreviation	APC1	APC2	APC3	MFTC	–	PNC2	–	–
HGNC, UniProt	SLC25A24, Q6NUK1	SLC25A23, Q9BV35	SLC25A25, Q6KCM7	SLC25A32, Q9H2D1	SLC25A33, Q9BSK2	SLC25A36, Q96CQ1	SLC25A41, Q8N5S1	SLC25A43, Q8WUT9

Mitochondrial uncoupling proteins

Overview

Mitochondrial uncoupling proteins allow dissipation of the mitochondrial proton gradient associated with thermogenesis and regulation of radical formation.

Nomenclature	Uncoupling protein 1	Uncoupling protein 2	Uncoupling protein 3
Systematic nomenclature	SLC25A7	SLC25A8	SLC25A9
Common abbreviation	UCP1	UCP2	UCP3
HGNC, UniProt	UCP1, P25874	UCP2, P55851	UCP3, P55916
Stoichiometry	H+ (in)	H+ (in)	H+ (in)

Nomenclature	Uncoupling protein 4	Uncoupling protein 5	KMCP1
Systematic nomenclature	SLC25A27	SLC25A14	SLC25A30
Common abbreviation	UCP4	UCP5	–
HGNC, UniProt	SLC25A27, O95847	SLC25A14, O95258	SLC25A30, Q5SVS4
Stoichiometry	H+ (in)	H+ (in)	–

Miscellaneous SLC25 mitochondrial transporters

Overview

Many of the transporters identified below have yet to be assigned functions and are currently regarded as orphans.

Nomenclature	mitochondrial carrier 1	mitochondrial carrier 2	Mitoferrin1	Mitoferrin2
Systematic nomenclature	SLC25A49	SLC25A50	SLC25A37	SLC25A28
HGNC, UniProt	MTCH1, Q9NZJ7	MTCH2, Q9Y6C9	SLC25A37, Q9NYZ2	SLC25A28, Q96A46

Nomenclature	solute carrier family 25, member 51	solute carrier family 25, member 52	solute carrier family 25, member 53	–
Systematic nomenclature	SLC25A51	SLC25A52	SLC25A53	SLC25A46
HGNC, UniProt	SLC25A51, Q9H1U9	SLC25A52, Q3SY17	SLC25A53, Q5H9E4	SLC25A46, Q96AG3

SLC26 family of anion exchangers

Overview

Along with the SLC4 family, the SLC26 family acts to allow movement of monovalent and divalent anions across cell membranes. The predicted topology is of 10–14 TM domains with intracellular C- and N-termini, probably existing as dimers. Within the family, subgroups may be identified on the basis of functional differences, which appear to function as anion exchangers and anion channels (SLC26A7 and SLC26A9).

Selective sulphate transporters

Nomenclature	Sat-1	DTDST
Systematic nomenclature	SLC26A1	SLC26A2
HGNC, UniProt	SLC26A1, Q9H2B4	SLC26A2, P50443
Substrates	SO42-, oxalate	SO42-
Stoichiometry	SO42- (in): anion (out)	1 SO42- (in): 2 Cl- (out)

Chloride/bicarbonate exchangers

Nomenclature	DRA	Pendrin	PAT-1
Systematic nomenclature	SLC26A3	SLC26A4	SLC26A6
HGNC, UniProt	SLC26A3, P40879	SLC26A4, O43511	SLC26A6, Q9BXS9
Substrates	Cl-	Cl-, HCO3-, formate, I-, OH-	Cl-, HCO3-, SO42-, oxalate, formate, I-, OH-
Stoichiometry	2 Cl- (in): 1 HCO3- (out) or 2 Cl- (in): 1 OH- (out)	Unknown	1 SO42- (in): 2 HCO3- (out) or 1 Cl- (in): 2 HCO3- (out)

Anion channels

Systematic nomenclature	SLC26A7	SLC26A9
HGNC, UniProt	SLC26A7, Q8TE54	SLC26A9, Q7LBE3
Substrates	NO3- >> Cl- = Br- = I- > SO42- = L-glutamic acid	I- > Br- > NO3- > Cl- > L-glutamic acid
Functional characteristics	Voltage- and time-independent current, linear I-V relationship 315	Voltage- and time-independent current, linear I-V relationship 314
Comment	–	SLC26A9 has been suggested to operate in two additional modes as a Cl--HCO3- exchanger and as a Na+-anion cotransporter 313

Other SLC26 anion exchangers

Nomenclature	Prestin	Tat1	–	KBAT
Systematic nomenclature	SLC26A5	SLC26A8	SLC26A10	SLC26A11
Common abbreviation	–	–	–	KBAT
HGNC, UniProt	SLC26A5, P58743	SLC26A8, Q96RN1	SLC26A10, Q8NG04	SLC26A11, Q86WA9
Substrates	Cl-, HCO3-	Cl-, SO42-, oxalate	–	HSO4-
Stoichiometry	Unknown	Unknown	Unknown	Unknown
Comment	Prestin has been suggested to function as a molecular motor, rather than a transporter	–	SLC26A10 is a possible pseudogene	–

SLC27 family of fatty acid transporters

Overview

Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1-6). They have at least one, and possibly six 319,325, transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) 317,322,323. These transporters are unusual in that they appear to express intrinsic very long-chain acyl-CoA synthetase (EC 6.2.1.-, EC 6.2.1.7) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1-4 and -6 transport long- and very long-chain fatty acids, while FATP5 transports long-chain fatty acids as well as bile acids 321,325.

Nomenclature	Fatty acid transport protein 1	Fatty acid transport protein 2	Fatty acid transport protein 3	Fatty acid transport protein 4	Fatty acid transport protein 5	Fatty acid transport protein 6
Systematic nomenclature	SLC27A1	SLC27A2	SLC27A3	SLC27A4	SLC27A5	SLC27A6
Common abbreviation	FATP1	FATP2	FATP3	FATP4	FATP5	FATP6
HGNC, UniProt	SLC27A1, Q6PCB7	SLC27A2, O14975	SLC27A3, Q5K4L6	SLC27A4, Q6P1M0	SLC27A5, Q9Y2P5	SLC27A6, Q9Y2P4
Endogenous substrates	arachidonic acid > palmitic acid > oleic acid > butyric acid 325, palmitic acid > oleic acid > γ-linolenic acid > octanoic acid 318	–	–	palmitic acid > oleic acid > butyric acid, γ-linolenic acid > arachidonic acid 326, palmitic acid, oleic acid > γ-linolenic acid > octanoic acid 318	–	palmitic acid > oleic acid > γ-linolenic acid > octanoic acid 318
Comment	–	–	–	FATP4 is genetically linked to restrictive dermopathy	–	–

Comments

Although the stoichiometry of fatty acid transport is unclear, it has been proposed to be facilitated by the coupling of fatty acid transport to conjugation with coenzyme A to form fatty acyl CoA esters. Small molecule inhibitors of FATP2 320,324 and FATP4 316,327, as well as bile acid inhibitors of FATP5 327, have been described; analysis of the mechanism of action of some of these inhibitors suggests that transport may be selectively inhibited without altering enzymatic activity of the FATP.

C1-BODIPY-C12 accumulation has been used as a non-selective index of fatty acid transporter activity.

FATP2 has two variants: Variant 1 encodes the full-length protein, while Variant 2 encodes a shorter isoform missing an internal protein segment. FATP6 also has two variants: Variant 2 encodes the same protein as Variant 1 but has an additional segment in the 5' UTR.

SLC28 and SLC29 families of nucleoside transporters

Overview

Nucleoside transporters are divided into two families, the sodium-dependent, solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29), where the endogenous substrates are nucleosides.

SLC28 family

Overview

SLC28 family members have 13 TM segments with cytoplasmic N-termini and extracellular C-termini.

Nomenclature	CNT1	CNT2	CNT3
Systematic nomenclature	SLC28A1	SLC28A2	SLC28A3
Common abbreviation	CNT1	CNT2	CNT3
HGNC, UniProt	SLC28A1, O00337	SLC28A2, O43868	SLC28A3, Q9HAS3
Endogenous substrates	adenosine, uridine, thymidine, cytidine	adenosine, inosine, guanosine, thymidine	adenosine, inosine, uridine, guanosine, thymidine, cytidine
Substrates	gemcitabine, zidovudine, zalcitabine	formycin B, cladribine, fludarabine, vidarabine, didanosine	5-fluorouridine, zebularine, formycin B, gemcitabine, cladribine, floxuridine, zidovudine, zalcitabine, didanosine
Stoichiometry	1 Na+: 1 nucleoside (in)	1 Na+: 1 nucleoside (in)	2 Na+: 1 nucleoside (in)

Comments

A further two Na⁺-dependent (stoichiometry 1 Na⁺: 1 nucleoside (in)) nucleoside transporters have been defined on the basis of substrate and inhibitor selectivity: CNT4 (N4/cit, which transports uridine, thymidine and guanosine) and CNT5 (N5/csg, which transports guanosine and adenosine, and may be inhibited by NBTI).

SLC29 family

Overview

SLC29 family members appear to be composed of 11 TM segments with cytoplasmic N-termini and extracellular C-termini. ENT1 and ENT2 are cell-surface transporters, while ENT3 is intracellular, possibly lysosomal 328. ENT1-3 are described as broad-spectrum nucleoside transporters.

Nomenclature	Equilibrative nucleoside transporter 1	Equilibrative nucleoside transporter 2	Equilibrative nucleoside transporter 3	Plasma membrane monoamine transporter
Systematic nomenclature	SLC29A1	SLC29A2	SLC29A3	SLC29A4
Common abbreviation	ENT1	ENT2	ENT3	PMAT
HGNC, UniProt	SLC29A1, Q99808	SLC29A2, Q14542	SLC29A3, Q9BZD2	SLC29A4, Q7RTT9
Endogenous substrates	adenosine 335, inosine 335, hypoxanthine 335, uridine 335, guanosine 335, thymine 335, thymidine 335, cytidine 335, adenine 335	adenosine, inosine, hypoxanthine, uridine, guanosine, thymidine	adenosine 328, inosine 328, uridine 328, guanosine 328, thymidine 328, adenine 328	5-HT 329, dopamine 329, histamine 329, tyramine 329
Substrates	2-chloroadenosine, formycin B, tubercidin, gemcitabine, cladribine, floxuridine, pentostatin, vidarabine, cytarabine, zalcitabine, didanosine	2-chloroadenosine, formycin B, tubercidin, gemcitabine, cladribine, vidarabine, zidovudine, cytarabine	cordycepin 328, zebularine 328, tubercidin 328, cladribine 328, floxuridine 328, fludarabine 328, zidovudine 328, zalcitabine 328, didanosine 328	tetraethylammonium 329, MPP+ 329
Inhibitors (pIC50)	NBTI (pKi 9.7), draflazine (pKi 9.5), KF24345 (pKi 9.4) 330, NBTGR (pKi 9.3), dilazep (pKi 9.0), dipyridamole (pKi 8.5)	–	–	cimetidine 329, quinidine 329, quinine 329, rhodamine123 329, verapamil 329
Radioligands (Kd)	[3H]NBTI (5x10-10 M)	–	–	–
Stoichiometry	Equilibrative	Equilibrative	Equilibrative	Equilibrative
Comment	ENT1 has 100-1000-fold lower affinity for nucleobases as compared with nucleosides 335., The affinities of draflazine, dilazep, KF24345 and dipyridamole at ENT1 transporters are species dependent, exhibiting lower affinity at rat transporters than at human transporters 330,333., The loss of ENT1 activity in ENT1-null mice has been associated with a hypermineralization disorder similar to human diffuse idiopathic skeletal hyperostosis 334	–	Defects in SLC29A3 have been implicated in Histiocytosis-lymphadenopathy plus syndrome (OMIM:602782) and lysosomal storage diseases 331,332	–

SLC30 zinc transporter family

Overview

Along with the SLC39 family, SLC30 transporters regulate the movement of zinc ions around the cell. In particular, these transporters remove zinc ions from the cytosol, allowing accumulation into intracellular compartments or efflux through the plasma membrane. ZnT1 is thought to be placed on the plasma membrane extruding zinc, while ZnT3 is associated with synaptic vesicles and ZnT4 and ZnT5 are linked with secretory granules. Membrane topology predictions suggest a multimeric assembly, potentially heteromultimeric 337, with subunits having six TM domains, and both termini being cytoplasmic. Dityrosine covalent linking has been suggested as a mechanism for dimerisation, particularly for ZnT3 336. The mechanism for zinc transport is unknown.

Nomenclature	Systematic nomenclature	Common abbreviation	HGNC, UniProt
Zinc transporter 1	SLC30A1	ZnT1	SLC30A1, Q9Y6M5
Zinc transporter 2	SLC30A2	ZnT2	SLC30A2, Q9BRI3
Zinc transporter 3	SLC30A3	ZnT3	SLC30A3, Q99726
Zinc transporter 4	SLC30A4	ZnT4	SLC30A4, O14863
Zinc transporter 5	SLC30A5	ZnT5	SLC30A5, Q8TAD4
Zinc transporter 6	SLC30A6	ZnT6	SLC30A6, Q6NXT4
Zinc transporter 7	SLC30A7	ZnT7	SLC30A7, Q8NEW0
Zinc transporter 8	SLC30A8	ZnT8	SLC30A8, Q8IWU4
Zinc transporter 9	SLC30A9	ZnT9	SLC30A9, Q6PML9
Zinc transporter 10	SLC30A10	ZnT10	SLC30A10, Q6XR72

Comments

ZnT8/SLC30A8 is described as a type 1 diabetes susceptibility gene.

Zinc fluxes may be monitored through the use of radioisotopic Zn-65 or the fluorescent dye FluoZin 3.

SLC31 family of copper transporters

Overview

SLC31 family members, alongside the Cu-ATPases are involved in the regulation of cellular copper levels. The CTR1 transporter is a cell-surface transporter to allow monovalent copper accumulation into cells, while CTR2 appears to be a vacuolar/vesicular transporter 341. Functional copper transporters appear to be trimeric with each subunit having three TM regions and an extracellular N-terminus. CTR1 is considered to be a higher affinity copper transporter compared to CTR2. The stoichiometry of copper accumulation is unclear, but appears to be energy-independent 340.

Nomenclature	Copper transporter 1	Copper transporter 2
Systematic nomenclature	SLC31A1	SLC31A2
Common abbreviation	CTR1	CTR2
HGNC, UniProt	SLC31A1, O15431	SLC31A2, O15432
Endogenous substrates	copper 340	copper
Substrates	cisplatin 339	cisplatin 338
Stoichiometry	Unknown	Unknown

Comments

Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations 340.

SLC32 vesicular inhibitory amino acid transporter

Overview

The vesicular inhibitory amino acid transporter, VIAAT (also termed the vesicular GABA transporter VGAT), which is the sole representative of the SLC32 family, transports GABA, or glycine, into synaptic vesicles 343,344, and is a member of the structurally-defined amino acid-polyamine-organocation/APC clan composed of SLC32, SLC36 and SLC38 transporter families (see 349). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N- and C-termini 347. However, an alternative 9TM structure with the N terminus facing the cytoplasm and the C terminus residing in the synaptic vesicle lumen has subsequently been reported 346. VIAAT acts as an antiporter for inhibitory amino acids and protons. The accumulation of GABA and glycine within vesicles is driven by both the chemical (ΔpH) and electrical (Δψ) components of the proton electrochemical gradient (Δμ_H+) established by a vacuolar H⁺-ATPase 347. However, one study, 345, presented evidence that VIAAT is instead a Cl^-/GABA co-transporter. VIAAT co-exists with VGLUT1 (SLC17A7), or VGLUT2 (SLC17A6), in the synaptic vesicles of selected nerve terminals 342,351. VIAAT knock out mice die between embryonic day 18.5 and birth 350. In cultures of spinal cord neurones established from earlier embryos, the co-release of of GABA and glycine from synaptic vesicles is drastically reduced, providing direct evidence for the role of VIAAT in the sequestration of both transmitters 348,350.

Nomenclature	Vesicular inhibitory amino acid transporter
Systematic nomenclature	SLC32A1
Common abbreviation	VIAAT
HGNC, UniProt	SLC32A1, Q9H598
Endogenous substrates	glycine, β-alanine, γ-hydroxybutyric acid, GABA (Km 5x10-3 M) 347
Inhibitors (pIC50)	vigabatrin (2.1) 347
Stoichiometry	1 amino acid (in): 1 H+ (out) 344 or 1 amino acid: 2Cl- (in) 345

SLC33 acetylCoA transporter

Overview

Acetylation of proteins is a post-translational modification mediated by specific acetyltransferases, using the donor acetyl CoA. SLC33A1/AT1 is a putative 11 TM transporter present on the endoplasmic reticulum, expressed in all tissues, but particularly abundant in the pancreas 353, which imports cytosolic acetyl CoA into these intracellular organelles.

Nomenclature	AcetylCoA transporter
Systematic nomenclature	SLC33A1
Common abbreviation	ACATN1
HGNC, UniProt	SLC33A1, O00400
Endogenous substrates	acetyl CoA
Radioligands (Kd)	[14C]acetylCoA
Stoichiometry	Unknown

Comments

In heterologous expression studies, acetyl CoA transport through AT1 was inhibited by coenzyme A, but not acetic acid, ATP or UDP-galactose 352. A loss-of-function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, 354), although this observation could not be replicated in a subsequent study 355.

SLC34 family of sodium phosphate co-transporters

Overview

The SLC34 family are sometimes referred to as Type II sodium-phosphate co-transporters, alongside Type I (SLC17 family) and Type III (SLC20 family) transporters. Topological modelling suggests eight TM domains with C- and N- termini in the cytoplasm, and a re-entrant loop at TM7/8. SLC34 family members are expressed on the apical surfaces of epithelia in the intestine and kidneys to regulate body phosphate levels, principally NaPi-IIa and NaPi-IIb, respectively. NaPi-IIa and NaPi-IIb are electrogenic, while NaPiIIc is electroneutral 356.

Nomenclature	Sodium phosphate 1	Sodium phosphate 2	Sodium phosphate 3
Systematic nomenclature	SLC34A1	SLC34A2	SLC34A3
Common abbreviation	NaPi-IIa	NaPi-IIb	NaPi-IIc
HGNC, UniProt	SLC34A1, Q06495	SLC34A2, O95436	SLC34A3, Q8N130
Stoichiometry	3 Na+: 1 HPO42- (in) 357	3 Na+: 1 HPO42- (in) 356	2 Na+: 1 HPO42- (in) 356

Comments

These transporters can be inhibited by PFA, in contrast to type III sodium-phosphate cotransporters, the SLC20 family.

SLC35 family of nucleotide sugar transporters

Overview

Glycoprotein formation in the Golgi and endoplasmic reticulum relies on the accumulation of nucleotide-conjugated sugars via the SLC35 family of transporters. These transporters have a predicted topology of 10 TM domains, with cytoplasmic termini, and function as exchangers, swopping nucleoside monophosphates for the corresponding nucleoside diphosphate conjugated sugar. Five subfamilies of transporters have been identified on the basis of sequence similarity, namely SLC35A1, SLC35A2, SLC35A3, SLC35A4 and SLC35A5; SLC35B1, SLC35B2, SLC35B3 and SLC35B4; SLC35C1 and SLC35C2; SLC35D1, SL35D1, SLC35D2 and SLC35D3, and the subfamily of orphan SLC35 transporters, SLC35E1-4 and SLC35F1-5.

Nomenclature	CMP-sialic acid transporter	UDP-galactose transporter	UDP-N-acetylglucosamine transporter	MGC2541	FLJ11130
Systematic nomenclature	SLC35A1	SLC35A2	SLC35A3	SLC35A4	SLC35A5
HGNC, UniProt	SLC35A1, P78382	SLC35A2, P78381	SLC35A3, Q9Y2D2	SLC35A4, Q96G79	SLC35A5, Q9BS91
Substrates	CMP-sialic acid 359	UDP N-acetyl-glucosamine 361,366, UDP-galactose 361,366	UDP N-acetyl-glucosamine 362	–	–

Nomenclature	UGTREL1	PAPS transporter 1	PAPS transporter 2	YEA
Systematic nomenclature	SLC35B1	SLC35B2	SLC35B3	SLC35B4
HGNC, UniProt	SLC35B1, P78383	SLC35B2, Q8TB61	SLC35B3, Q9H1N7	SLC35B4, Q969S0
Substrates	–	A3P5PS 364	A3P5PS 363	UDP N-acetyl-glucosamine 358, UDP-xylose 358

Nomenclature	GDP-Fucose transporter	OVCOV1	UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter	HFRC1	FRCL1
Systematic nomenclature	SLC35C1	SLC35C2	SLC35D1	SLC35D2	SLC35D3
HGNC, UniProt	SLC35C1, Q96A29	SLC35C2, Q9NQQ7	SLC35D1, Q9NTN3	SLC35D2, Q76EJ3	SLC35D3, Q5M8T2
Substrates	GDP-fucose 365	–	UDP-glucuronic acid 367, UDP-N-acetylgalactosamine 367	UDP-N-acetylgalactosamine 360	–

Nomenclature	–	–	solute carrier family 35, member E2B	–	–
Systematic nomenclature	SLC35E1	SLC35E2	SLC35E2B	SLC35E3	SLC35E4
HGNC, UniProt	SLC35E1, Q96K37	SLC35E2, P0CK97	SLC35E2B, P0CK96	SLC35E3, Q7Z769	SLC35E4, Q6ICL7
Comment	Orphan transporter	Orphan transporter	–	Orphan transporter	Orphan transporter

Nomenclature	–	–	–	–	–	solute carrier family 35, member F6
Systematic nomenclature	SLC35F1	SLC35F2	SLC35F3	SLC35F4	SLC35F5	SLC35F6
HGNC, UniProt	SLC35F1, Q5T1Q4	SLC35F2, Q8IXU6	SLC35F3, Q8IY50	SLC35F4, A4IF30	SLC35F5, Q8WV83	SLC35F6, Q8N357
Comment	Orphan transporter	Orphan transporter	Orphan transporter	Orphan transporter	Orphan transporter	–

Nomenclature	solute carrier family 35, member G1	solute carrier family 35, member G3	solute carrier family 35, member G4	solute carrier family 35, member G5	solute carrier family 35, member G6
Systematic nomenclature	SLC35G1	SLC35G3	SLC35G4	SLC35G5	SLC35G6
HGNC, UniProt	SLC35G1, Q2M3R5	SLC35G3, Q8N808	SLC35G4, P0C7Q5	SLC35G5, Q96KT7	SLC35G6, P0C7Q6

SLC36 family of proton-coupled amino acid transporters

Overview

The SLC36 family of proton-coupled amino acid transporters (or PAT) is highly expressed in the intestine and kidney, having roles in the disposition of amino acids 383. PAT1 is found on the gut epithelia luminal surface accumulating dietary amino acids, and additionally in lysosomal membranes where it likely functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis 369,382. PAT2 is found at the apical membrane of the kidney proximal tubule 372. PAT1 and PAT2 are predicted to have 11 TM domains with intracellular N-termini 370,382.

Nomenclature	Proton-coupled Amino acid Transporter 1	Proton-coupled Amino acid Transporter 2	Proton-coupled Amino acid Transporter 3	Proton-coupled Amino acid Transporter 4
Systematic nomenclature	SLC36A1	SLC36A2	SLC36A3	SLC36A4
Common abbreviation	PAT1	PAT2	PAT3	PAT4
HGNC, UniProt	SLC36A1, Q7Z2H8	SLC36A2, Q495M3	SLC36A3, Q495N2	SLC36A4, Q6YBV0
Endogenous substrates	L-alanine, glycine, GABA, β-alanine, taurine, L-proline, D-serine, D-cysteine, D-proline, D-alanine, trans-4-hydroxy-proline, sarcosine	L-alanine, glycine, β-alanine, L-proline, trans-4-hydroxy-proline, sarcosine	–	L-tryptophan 381, L-proline 381
Substrates	THIP 378, betaine, L-azetidine-2-carboxylate 377, MeAIB 373, β-guanidinopropionic acid, THPO 379, 5-aminolevulinic acid, vigabatrin 368	L-azetidine-2-carboxylate 377, MeAIB 374	–	–
Inhibitors (pIC50)	5-hydroxy-L-tryptophan (pKi 3.0) 380, indole-3-propionic acid (pKi 2.3) 380, L-tryptophan (pKi 2.3) 380, 5-HT (pKi 2.2) 380	5-hydroxy-L-tryptophan (2.8) 375, α-methyl-D,L-tryptophan (2.5) 375	–	–
Stoichiometry	1 H+: 1 amino acid (in)	1 H+: 1 amino acid (in)	Unknown	Unknown
Comment	[3H] or [14C] labelled substrates as listed above are used as probes	[3H] or [14C] labelled substrates as listed above are used as probes	–	–

Comments

Both PAT1 and PAT2 can also function as an electroneutral transport system for H⁺ and fatty acids including acetic acid, propanoic acid and butyric acid 376.

Loss-of-function mutations in PAT2 lead to iminoglycinuria and hyperglycinuria in man 371.

SLC37 family of phosphosugar/phosphate exchangers

Overview

The family of sugar-phosphate exchangers pass particular phosphorylated sugars across intracellular membranes, exchanging for inorganic phosphate. Of the family of sugar phosphate transporters, most information is available on SPX4, the glucose-6-phosphate transporter. This is a 10 TM domain protein with cytoplasmic termini and is associated with the endoplasmic reticulum, with tissue-specific splice variation.

Nomenclature	Glycerol-3-phosphate transporter	SPX2	SPX3	Glucose-6-phosphate transporter
Systematic nomenclature	SLC37A1	SLC37A2	SLC37A3	SLC37A4
Common abbreviation	SPX1	–	–	SPX4
HGNC, UniProt	SLC37A1, P57057	SLC37A2, Q8TED4	SLC37A3, Q8NCC5	SLC37A4, O43826
Endogenous substrates	glucose 6-phosphate, glycerol 3-phosphate	glucose 6-phosphate	–	glucose 6-phosphate
Stoichiometry	Glucose 6-phosphate (in): phosphate (out) 386	Glucose 6-phosphate (in): phosphate (out) 386	Unknown	Glucose 6-phosphate (in): phosphate (out) 385
Comment	–	–	–	Multiple polymorphisms have been described for the SLC37A4 gene, some of which associate with a glycogen storage disease 384

SLC38 family of sodium-dependent neutral amino acid transporters

Overview

The SLC38 family of transporters appears to be responsible for the functionally-defined system A and system N mechanisms of amino acid transport and are mostly expressed in the CNS. Two distinct subfamilies are identifiable within the SLC38 transporters. SNAT1, SNAT2 and SNAT4 appear to resemble system A transporters in accumulating neutral amino acids under the influence of the sodium gradient. SNAT3 and SNAT5 appear to resemble system N transporters in utilizing proton co-transport to accumulate amino acids. The predicted membrane topology is of 11 TM domains with an extracellular C-terminus and intracellular N-terminus 394.

System A-like transporters

Nomenclature	SNAT1	SNAT2	SNAT4
Systematic nomenclature	SLC38A1	SLC38A2	SLC38A4
Common abbreviation	SNAT1	SNAT2	SNAT4
HGNC, UniProt	SLC38A1, Q9H2H9	SLC38A2, Q96QD8	SLC38A4, Q969I6
Endogenous substrates	L-alanine > L-serine, L-glutamine, L-asparagine, L-histidine, L-cysteine, L-methionine > glycine, L-threonine, L-proline, L-tyrosine, L-valine 387	L-alanine, L-methionine > L-asparagine, L-glutamine, L-serine, L-proline, glycine > L-threonine, L-leucine, L-phenylalanine 391	L-histidine > L-arginine, L-alanine, L-asparagine, L-lysine > glycine, L-glutamine, L-serine, L-proline, L-leucine, L-phenylalanine 390
Substrates	MeAIB	MeAIB	MeAIB
Radioligands (Kd)	[14C]alanine, [3H]alanine	[14C]alanine, [3H]alanine	[14C]alanine, [14C]glycine, [3H]alanine, [3H]glycine
Stoichiometry	1 Na+: 1 amino acid (in) 387	1 Na+: 1 amino acid (in) 391	1 Na+: 1 neutral amino acid (in) 390
Comment	–	–	Transport of cationic amino acids by SNAT4 was sodium-independent 390

System N-like transporters

Nomenclature	SNAT3	SNAT5
Systematic nomenclature	SLC38A3	SLC38A5
Common abbreviation	SNAT3	SNAT5
HGNC, UniProt	SLC38A3, Q99624	SLC38A5, Q8WUX1
Endogenous substrates	L-histidine, L-glutamine > L-asparagine, L-alanine > L-glutamic acid 389	L-asparagine, L-serine, L-histidine, L-glutamine > glycine, L-alanine 393
Substrates	MeAIB	MeAIB
Radioligands (Kd)	[14C]glutamine, [3H]glutamine	[14C]histidine, [3H]histidine
Stoichiometry	1 Na+: 1 amino acid (in): 1 H+ (out) 388	1 Na+: 1 amino acid (in): 1 H+ (out) 393

Orphan SLC38 transporters

Nomenclature	SNAT6	SNAT7	–	–	PP1744	AVT2
Systematic nomenclature	SLC38A6	SLC38A7	SLC38A8	SLC38A9	SLC38A10	SLC38A11
Common abbreviation	SNAT6	SNAT7	–	–	–	–
HGNC, UniProt	SLC38A6, Q8IZM9	SLC38A7, Q9NVC3	SLC38A8, A6NNN8	SLC38A9, Q8NBW4	SLC38A10, Q9HBR0	SLC38A11, Q08AI6
Comment	–	SNAT7/SLC38A7 has been described to be a system N-like transporter allowing preferential accumulation of L-glutamine, L-histidine and L-asparagine 392	–	–	–	–

SLC39 family of metal ion transporters

Overview

Along with the SLC30 family, SLC39 family members regulate zinc movement in cells. SLC39 metal ion transporters accumulate zinc into the cytosol. Membrane topology modelling suggests the presence of eight TM regions with both termini extracellular or in the lumen of intracellular organelles. The mechanism for zinc transport for many members is unknown but appears to involve co-transport of bicarbonate ions 396,397.

Nomenclature	Zinc transporter 1	Zinc transporter 2	Zinc transporter 3	Zinc transporter 4	metal ion transporter 5	Zinc transporter 6	Zinc transporter 7
Systematic nomenclature	SLC39A1	SLC39A2	SLC39A3	SLC39A4	SLC39A5	SLC39A6	SLC39A7
Common abbreviation	ZIP1	ZIP2	ZIP3	ZIP4	ZIP5	ZIP6	ZIP7
HGNC, UniProt	SLC39A1, Q9NY26	SLC39A2, Q9NP94	SLC39A3, Q9BRY0	SLC39A4, Q6P5W5	SLC39A5, Q6ZMH5	SLC39A6, Q13433	SLC39A7, Q92504

Nomenclature	Zinc transporter 8	Zinc transporter 9	Zinc transporter 10	Zinc transporter 11	Zinc transporter 12	Zinc transporter 13	Zinc transporter 14
Systematic nomenclature	SLC39A8	SLC39A9	SLC39A10	SLC39A11	SLC39A12	SLC39A13	SLC39A14
Common abbreviation	ZIP8	ZIP9	ZIP10	ZIP11	ZIP12	ZIP13	ZIP14
HGNC, UniProt	SLC39A8, Q9C0K1	SLC39A9, Q9NUM3	SLC39A10, Q9ULF5	SLC39A11, Q8N1S5	SLC39A12, Q504Y0	SLC39A13, Q96H72	SLC39A14, Q15043
Substrates	Cd2+ 395,397	–	–	–	–	–	Cd2+ 396, Fe2+ 398, Mn2+ 396
Stoichiometry	1 Zn2+ (in): 2 HCO3- (in) 397	–	–	–	–	–	–

Comments

Zinc fluxes may be monitored through the use of radioisotopic Zn-65 or the fluorescent dye FluoZin 3.

The bicarbonate transport inhibitor DIDS has been reported to inhibit cation accumulation through ZIP14 396.

SLC40 iron transporter

Overview

Alongside the SLC11 family of proton-coupled metal transporters, ferroportin allows the accumulation of iron from the diet. Whilst SLC11A2 functions on the apical membrane, ferroportin acts on the basolateral side of the enterocyte, as well as regulating macrophage and placental iron levels. The predicted topology is of 12 TM domains, with intracellular termini 403, with the functional transporter potentially a dimeric arrangement 399,400.

Nomenclature	Ferroportin
Systematic nomenclature	SLC40A1
Common abbreviation	IREG1
HGNC, UniProt	SLC40A1, Q9NP59
Endogenous substrates	Fe2+
Stoichiometry	Unknown

Comments

Hepcidin (HAMP, P81172), cleaved into hepcidin-25 (HAMP, P81172) and hepcidin-20 (HAMP, P81173), is a small protein that increases upon inflammation, binds to ferroportin to regulate its cellular distribution and degradation. Gene disruption in mice results in embryonic lethality 402, while loss-of-function mutations in man are associated with haemochromatosis 401.

SLC41 family of divalent cation transporters

Overview

By analogy with bacterial orthologues, this family is probably magnesium transporters. The prokaryote orthologue, MgtE, is responsible for uptake of divalent cations, while the heterologous expression studies of mammalian proteins suggest Mg²⁺ efflux 406, possibly as a result of co-expression of particular protein partners (see 407). Topological modelling suggests 10 TM domains with cytoplasmic C- and N- termini.

Systematic nomenclature	SLC41A1	SLC41A2	SLC41A3
Common abbreviation	MgtE	–	–
HGNC, UniProt	SLC41A1, Q8IVJ1	SLC41A2, Q96JW4	SLC41A3, Q96GZ6
Substrates	Zn2+ 404, Mg2+ 404, Ba2+ 404, Cd2+ 404, Co2+ 404, Cu2+ 404, Fe2+ 404, Sr2+ 404	Mg2+ 405, Ba2+ 405, Ni2+ 405, Co2+ 405, Fe2+ 405, Mn2+ 405	–
Stoichiometry	Unknown	Unknown	Unknown

SLC42 family of Rhesus glycoprotein ammonium transporters

Overview

LAT3 (SLC43A1) and LAT4 (SLC43A2) are transporters with system L amino acid transporter activity, along with the structurally and functionally distinct transporters LAT1 and LAT2 that are members of the SLC7 family. LAT3 and LAT4 contain 12 putative TM domains with both N and C termini located intracellularly. They transport neutral amino acids in a manner independent of Na⁺ and Cl^- and with two kinetic components 412,413. LAT3/SLC43A1 is expressed in human tissues at high levels in the pancreas, liver, skeletal muscle and fetal liver 412 whereas LAT4/SLC43A2 is primarily expressed in the placenta, kidney and peripheral blood leukocytes 413. SLC43A3 is expressed in vascular endothelial cells 414 but remains to be characterised.

Nomenclature	L-type amino acid transporter 3	L-type amino acid transporter 4	EEG1
Systematic nomenclature	SLC43A1	SLC43A2	SLC43A3
Common abbreviation	LAT3	LAT4	–
HGNC, UniProt	SLC43A1, O75387	SLC43A2, Q8N370	SLC43A3, Q8NBI5
Substrates	L-isoleucine, L-leucine, L-phenylalanine, L-valinol, L-leucinol, L-phenylalaninol, L-valine, L-methionine	L-isoleucine, L-leucine, L-phenylalanine, L-valinol, L-leucinol, L-valine, L-methionine	–
Stoichiometry	Operates by facilitative diffusion	Operates by facilitative diffusion	–

Comments

Covalent modification of LAT3 by N-ethylmaleimide inhibits its function 412 and at LAT4 inhibits the low-, but not high-affinity component of transport 413.

SLC44 choline transporter-like family

Overview

Members of the choline transporter-like family are encoded by five genes (CTL1-CTL5) with further diversity occurring through alternative splicing of CTL1, 4 and 5 423. CTL family members are putative 10TM domain proteins with extracellular termini that mediate Na⁺-independent transport of choline with an affinity that is intermediate to that of the high affinity choline transporter CHT1 (SLC5A7) and the low affinity organic-cation transporters [OCT1 (SLC22A1) and OCT2 (SLC22A2)] 420. CLT1 is expressed almost ubiquitously in human tissues 425 and mediates choline transport across the plasma and mitochondrial membranes 419. Transport of choline by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; 417) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated 417,422. CTL3-5 remain to be characterized functionally.

Nomenclature	Choline transporter-like 1	Choline transporter-like 2	Choline transporter-like 3	Choline transporter-like 4	Choline transporter-like 5
Systematic nomenclature	SLC44A1	SLC44A2	SLC44A3	SLC44A4	SLC44A5
Common abbreviation	CTL1	CTL2	CTL3	CTL4	CTL5
HGNC, UniProt	SLC44A1, Q8WWI5	SLC44A2, Q8IWA5	SLC44A3, Q8N4M1	SLC44A4, Q53GD3	SLC44A5, Q8NCS7
Substrates	choline	choline	–	–	–
Inhibitors (pIC50)	hemicholinium-3 (pKi 3.5 – 4.5)	–	–	–	–
Stoichiometry	Unknown: uptake enhanced in the absence of extracellular Na+, reduced by membrane depolarization, extracellular acidification and collapse of plasma membrane H+ electrochemical gradient	–	–	–	–

Comments

Data tabulated are features observed for CLT1 endogenous to: rat astrocytes 416; rat renal tubule epithelial cells 426; human colon carcinoma cells 418; human keratinocytes 424 and human neuroblastoma cells 427. Choline uptake by CLT1 is inhibited by numerous organic cations (e.g. 416,426,427). In the guinea-pig, CTL2 is a target for antibody-induced hearing loss 421 and in man, a polymorphism in CTL2 constitutes the human neutrophil alloantigen-3a (HNA-3a; 415).

SLC45 family of putative sugar transporters

Overview

Members of the SLC45 family remain to be fully characterised. SLC45A1 was initially identified in the rat brain, particularly predominant in the hindbrain, as a proton-associated sugar transport, induced by hypercapnia 430. The protein is predicted to have 12TM domains, with intracellular termini. The SLC45A2 gene is thought to encode a transporter protein that mediates melanin synthesis. Mutations in SLC45A2 are a cause of oculocutaneous albinism type 4 (e.g. 429), and polymorphisms in this gene are associated with variations in skin and hair color (e.g. 428).

Systematic nomenclature	SLC45A1	SLC45A2	SLC45A3	SLC45A4
HGNC, UniProt	SLC45A1, Q9Y2W3	SLC45A2, Q9UMX9	SLC45A3, Q96JT2	SLC45A4, Q5BKX6
Substrates	L-glucose (Rat) 430, Galactose (Rat) 430	–	–	–
Stoichiometry	Unknown; increased at acid pH 430.	–	–	–

SLC46 family of folate transporters

Overview

Based on the proptypical member of this family, PCFT, this family includes proton-driven transporters with 11 TM segments. SLC46A1 has been described to act as an intestinal proton-coupled high-affinity folic acid transporter 432, with lower affinity for heme. folic acid accumulation is independent of Na⁺ or K⁺ ion concentrations, but driven by extracellular protons with an as yet undefined stoichiometry.

Nomenclature	Proton-coupled folate transporter	Thymic stromal co-transporter	–
Systematic nomenclature	SLC46A1	SLC46A2	SLC46A3
Common abbreviation	PCFT	TSCOT	–
HGNC, UniProt	SLC46A1, Q96NT5	SLC46A2, Q9BY10	SLC46A3, Q7Z3Q1
Substrates	folic acid (1.3μM) > heme (>100 μM) 431	–	–
Endogenous substrates	N5-methyltetrafolate 432	–	–
Substrates	methotrexate 432, N-formyltetrahydrofolate, pemetrexed	–	–
Radioligands (Kd)	[3H]folic acid, [3H]folinic acid, [3H]methotrexate, [3H]N5-methylfolate, [3H]pemetrexed	–	–
Comment	Loss-of-function mutations in PCFT (SLC46A1) are the molecular basis for hereditary folate maladsorption 433	Function as-yet unknown	Function as-yet unknown

SLC47 family of multidrug and toxin extrusion transporters

Overview

These proton:organic cation exchangers are predicted to have 13 TM segments 443 and are suggested to be responsible for excretion of many drugs in the liver and kidneys.

Nomenclature	Multi antimicrobial extrusion protein	MATE2
Systematic nomenclature	SLC47A1	SLC47A2
Common abbreviation	MATE1	MATE2-K
HGNC, UniProt	SLC47A1, Q96FL8	SLC47A2, Q86VL8
Endogenous substrates	creatine 439, thiamine 439	creatine 439, thiamine 439
Substrates	cimetidine 437, quinidine 439, paraquat 434, cephradine 439, cephalexin 439	cimetidine 436, MPP+ 436, N1-methylnicotinamide 436, metformin 436, guanidine 439, procainamide 436, acyclovir 439
(Sub)family-selective inhibitors (pIC50)	pyrimethamine (pKi 6.8), cimetidine (pKi 6.0) 441	pyrimethamine (pKi 6.3 - Mouse) 435, cimetidine (pKi 5.1) 441
Radioligands (Kd)	[14C]metformin 439,440, [14C]TEA 438,440	[14C]TEA 439

Comments

DAPI has been used to allow quantification of MATE1 and MATE2-mediated transport activity 442. MATE2 and MATE2-B are inactive splice variants of MATE2-K 436.

SLC48 heme transporter

Overview

HRG1 has been identified as a cell surface and lysosomal heme transporter 445. In addition, evidence suggests this 4TM-containing protein associates with the V-ATPase in lysosomes 444. Recent studies confirm its lysosomal location and demonstrate that it has an important physiological function in macrophages ingesting senescent red blood cells (erythrophagocytosis), recycling heme (released from the red cell hemoglobin) from the phagolysosome into the cytosol, where the heme is subsequently catabolized to recycle the iron 446.

Nomenclature	Heme transporter
Systematic nomenclature	SLC48A1
Common abbreviation	HRG1
HGNC, UniProt	SLC48A1, Q6P1K1

SLC49 family of FLVCR-related heme transporters

Overview

FLVCR1 was initially identified as a cell-surface attachment site for feline leukemia virus subgroup C 455, and later identified as a cell surface accumulation which exports heme from the cytosol 452. A recent study indicates that an isoform of FLVCR1 is located in the mitochondria, the site of the final steps of heme synthesis, and appears to transport heme into the cytosol 448. FLVCR-mediated heme transport is essential for erythropoiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (posterior column ataxia with retinitis pigmentosa (PCARP) 453.There are three paralogs of FLVCR1 in the human genome.

FLVCR2, most similar to FLVCR1 450, has been reported to function as a heme importer 449. In addition, a congenital syndrome of proliferative vasculopathy and hydranencephaly, also known as Fowler's syndrome, is associated with a loss-of-function mutation in FLVCR2 451.

The functions of the other two members of the SLC49 family, MFSD7 and DIRC2, are unknown, although DIRC2 has been implicated in hereditary renal carcinomas 447.

Nomenclature	Feline leukemia virus subgroup C cellular receptor family, member 1	Feline leukemia virus subgroup C cellular receptor family, member 2	Major facilitator superfamily domain containing 7	Disrupted in renal carcinoma 2
Systematic nomenclature	SLC49A1	SLC49A2	SLC49A3	SLC49A4
Common abbreviation	FLVCR1	FLVCR2	MFSD7	DIRC2
HGNC, UniProt	FLVCR1, Q9Y5Y0	FLVCR2, Q9UPI3	MFSD7, Q6UXD7	DIRC2, Q96SL1
Substrates	heme 452	heme 449	–	–
Stoichiometry	Unknown	Unknown	Unknown	Unknown

Comments

Non-functional splice alternatives of FLVCR1 have been implicated as a cause of a congenital red cell aplasia, Diamond Blackfan anemia 454.

SLC50 sugar transporter

Overview

A mouse stromal cell cDNA library was used to clone C2.3 457, later termed Rag1-activating protein 1, with a sequence homology predictive of a 4TM topology. The plant orthologues, termed SWEETs, appear to be 7 TM proteins, with extracellular N-termini, and the capacity for bidirectional flux of D-glucose 456. Expression of mouse SWEET in the mammary gland was suggestive of a role in Golgi lactose synthesis 456.

Nomenclature	SLC50 sugar exporter
Systematic nomenclature	SLC50A1
Common abbreviation	RAG1AP1
HGNC, UniProt	SLC50A1, Q9BRV3

SLC51 family of steroid-derived molecule transporters

Overview

The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the bile duct, small intestine and kidney, and elsewhere, as part of the enterohepatic circulation 458,460. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement 461. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons 458,460. OSTα/OSTβ heterodimers have been shown to transport [3H]taurocholic acid, [3H]DHEAS, [3H]estrone-3-sulphate, [3H]-pregnenolone sulphate and [3H]DHEAS 458,460,461. OSTα is suggested to be a seven TM protein, while OSTβ is a single TM ‘ancillary’ protein, both of which are thought to have intracellular C-termini 462. Bimolecular fluorescence complementation studies suggest the possibility of OSTα homo-oligomers, as well as OSTα/OSTβ hetero-oligomers 459,462.

Nomenclature	OSTα	OSTβ
Systematic nomenclature	SLC51A1	SLC51A1BP
HGNC, UniProt	SLC51A, Q86UW1	SLC51B, Q86UW2

SLC52 family of riboflavin transporters

Overview

riboflavin, also known as vitamin B2, is a precursor of the enzyme cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Riboflavin transporters are predicted to possess 10 or 11 TM segments.

Nomenclature	solute carrier family 52 (riboflavin transporter), member 1	solute carrier family 52 (riboflavin transporter), member 2	solute carrier family 52 (riboflavin transporter), member 3
Systematic nomenclature	SLC52A1	SLC52A2	SLC52A3
Common abbreviation	RFVT1	RFVT2	RFVT3
HGNC, UniProt	SLC52A1, Q9NWF4	SLC52A2, Q9HAB3	SLC52A3, Q9NQ40
Endogenous substrates	riboflavin (Km 1.38x10-9 M) 463	riboflavin (Km 9.8x10-10 M) 463	riboflavin (Km 3.3x10-10 M) 463
Stoichiometry	Unknown	Unknown	H+-dependent

Comments

Although expressed elsewhere, RFVT3 is found on the luminal surface of intestinal epithelium and is thought to mediate uptake of dietary riboflavin, while RFVT1 and RFVT2 are thought to allow movement from the epithelium into the blood.

SLCO family of organic anion transporting polypeptides

Overview

The SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below.

Nomenclature	OATP1A2	OATP1B1	OATP1B3	OATP1C1
Systematic nomenclature	SLCO1A2	SLCO1B1	SLCO1B3	SLCO1C1
HGNC, UniProt	SLCO1A2, P46721	SLCO1B1, Q9Y6L6	SLCO1B3, Q9NPD5	SLCO1C1, Q9NYB5
Endogenous substrates	PGE2, bilirubin, bile acids, steroid conjugates, thyroid hormones	bilirubin, bile acids, leukotrienes, steroid conjugates, thyroid hormones	CCK-8, LTC4, bilirubin, bile acids, steroid conjugates, thyroid hormones	steroid conjugates, thyroid hormones
Substrates	deltorphin II, rosuvastatin, BSP, talinolol, microcystin, fexofenadine, ouabain, antibiotics, anticancer drugs, beta blockers, fluoroquinolones, HIV protease inhibitors	rifampicin, BSP, fexofenadine, ACE inhibitors, anticancer drugs, antifungals, β-lactam antibiotics, bile acid derivatives and conjugates, endothelin receptor antagonists, HIV protease inhibitors, opioids, sartans, statins	erythromycin-A, rifampicin, BSP, amanitin, digoxin, phalloidin, saquinavir, fexofenadine, ouabain, anticancer drugs, β-lactam antibiotics, bile acid derivatives and conjugates, opioids, sartans, statins	BSP, statins
Inhibitors (pIC50)	naringin, rifampicin, rifamycin SV	cyclosporin A, gemfibrozil, glycyrrhizin, indocyanine Green, rifampicin, rifamycin SV, sildenafil	cyclosporin A, gemfibrozil, glycyrrhizin, rifampicin, rifamycin SV, sildenafil	DPDPE, probenecid, taurocholic acid
Radioligands (Kd)	[3H]BSP, [3H]DPDPE, [3H]estrone-3-sulphate	[3H]estradiol-17β-glucuronide, [3H]estrone-3-sulphate	[3H]BSP, [3H]CCK-8 (human, mouse, rat), [3H]estradiol-17β-glucuronide	[125I]thyroxine, [3H]BSP, [3H]estrone-3-sulphate
Comment	–	Other inhibitors include fibrates, flavonoids, glitazones and macrolide antibiotics. pravastatin is used as a probe	Other inhibitors include HIV protease inhibitors, glitazones and macrolide antibiotics	–

Nomenclature	OATP2A1	OATP2B1	OATP3A1
Systematic nomenclature	SLCO2A1	SLCO2B1	SLCO3A1
HGNC, UniProt	SLCO2A1, Q92959	SLCO2B1, O94956	SLCO3A1, Q9UIG8
Endogenous substrates	eicosanoids, prostaglandins	T4, dehydroepiandrosterone sulphate, estrone-3-sulphate	BQ123, vasopressin, prostaglandins, thyroid hormones
Substrates	synthetic prostaglandin derivatives	telmisartan, glibenclamide, amiodarone, bosentan, BSP, talinolol, aliskiren, fexofenadine, statins	–
Inhibitors (pIC50)	bromocresol green, BSP	gemfibrozil, glibenclamide, rifamycin SV	–
Radioligands (Kd)	[3H]PGE2	[3H]BSP, [3H]estrone-3-sulphate	[3H]estrone-3-sulphate, [3H]PGE2
Comment	Other inhibitors include NSAIDs	Other inhibitors include glitazones and citrus juices	–

Nomenclature	OATP4A1	OATP4C1	OATP5A1	OATP6A1
Systematic nomenclature	SLCO4A1	SLCO4C1	SLCO5A1	SLCO6A1
HGNC, UniProt	SLCO4A1, Q96BD0	SLCO4C1, Q6ZQN7	SLCO5A1, Q9H2Y9	SLCO6A1, Q86UG4
Endogenous substrates	bile acids, prostaglandins, steroid conjugates, thyroid hormones	cAMP, steroid conjugates, thyroid hormones	–	–
Substrates	penicillin G	anticancer drugs, cardiac glycosides, dipeptidyl peptidase-4 inhibitors	–	–
Radioligands (Kd)	[3H]estrone-3-sulphate	[3H]digoxin	–	–