Overview: Potassium channels are fundamental regulators of excitability. They control the frequency and the shape of action potential waveform, the secretion of hormones and neurotransmitters and cell membrane potential. Their activity may be regulated by voltage, calcium and neurotransmitters (and the signalling pathways they stimulate). They consist of a primary pore-forming α subunit often associated with auxiliary regulatory subunits. Because there are over 70 different genes encoding K channels α subunits in the human genome, it is beyond the scope of this guide to treat each subunit individually. Instead, channels have been grouped into families and subfamilies based on their structural and functional properties. Due to space constraints, the Ensembl ID for only one member of each subfamily is given. Ensembl information for the other subfamily members can be found from links therein. The three main families are the 2TM (two transmembrane domain), 4TM and 6TM families. A standardized nomenclature for potassium channels has been proposed by the NC-IUPHAR subcommittees on potassium channels (see Goldstein et al., 2005; Gutman et al., 2005; Kubo et al., 2005; Wei et al., 2005).
The 2TM family of K channels
The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (KIR2.x), the G protein-activated inward-rectifier K channels (KIR3.x) and the ATP-sensitive K channels [KIR6.x, which combine with sulphonylurea receptors (SUR)]. The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. KIR3.2 with KIR3.3).
| Subfamily group | KIR1.x | KIR2.x | KIR3.x | KIR4.x |
|---|---|---|---|---|
| Subtypes | KIR1.1 (ROMK1) | KIR2.1–2.4 (IRK1–4) | KIR3.1–3.4 (GIRK1–4) | KIR4.1–4.2 |
| Ensembl ID | ENSG00000151704 (KIR1.1) | ENSG00000123700 (KIR2.1) | ENSG00000162989 (KIR3.1) | ENSG00000177807 (KIR4.1) |
| Activators | – | – | PIP2, Gβγ | – |
| Inhibitors | – | [Mg2+]i, polyamines (internal) | – | – |
| Functional characteristic | Inward-rectifier current | IK1 in heart, ‘strong’ inward-rectifier current | G protein-activated inward-rectifier current | Inward-rectifier current |
| Subfamily group | KIR5.x | KIR6.x | KIR7.x |
|---|---|---|---|
| Subtypes | KIR5.1 | KIR6.1–6.2 (KATP) | KIR7.1 |
| Ensembl ID | ENSG00000153822 (KIR5.1) | ENSG00000121361 (KIR6.1) | ENSG00000115474 (KIR7.1) |
| Activators | – | Minoxidil, cromakalim, diazoxide, nicorandil | – |
| Inhibitors | – | Tolbutamide, glibenclamide | – |
| Functional characteristic | Inward-rectifier current | ATP-sensitive, inward-rectifier current | Inward-rectifier current |
| Associated subunits | – | SUR1, SUR2A, SUR2B | – |
The 4TM family of K channels
The 4TM family of K channels are thought to underlie many leak currents in native cells. They are open at all voltages and regulated by a wide array of neurotransmitters and biochemical mediators. The primary pore-forming α subunit contains two pore domains (indeed, they are often referred to as two-pore domain K channels or K2P), and so it is envisaged that they form functional dimers rather than the usual K channel tetramers. There is some evidence that they can form heterodimers within subfamilies (e.g. K2P3.1 with K2P9.1). There is no current, clear, consensus on nomenclature of 4TM K channels, nor on the division into subfamilies (see Goldstein et al., 2005). The suggested division into subfamilies, below, is based on similarities in both structural and functional properties within subfamilies.
| Subfamily group | ‘TWIK’ | ‘TREK’ | ‘TASK’ | ‘TALK’ | ‘THIK’ | ‘TRESK’ |
|---|---|---|---|---|---|---|
| Subtypes | K2P1.1 (TWIK1) K2P6.1 (TWIK2) K2P7.1 (KNCK7) | K2P2.1 (TREK1) K2P10.1 (TREK2) K2P4.1 (TRAAK) | K2P3.1 (TASK1) K2P9.1 (TASK3) K2P15.1 (TASK5) | K2P16.1 (TALK1) K2P5.1 (TASK2) K2P17.1 (TASK4) | K2P13.1 (THIK1) K2P12.1 (THIK2) | K2P18.1 (TRESK) |
| Ensembl ID | ENSG00000135750 (K2P1.1) | ENSG00000082482 (K2P2.1) | ENSG00000171301 (K2P3.1) | ENSG00000164626 (K2P5.1) | ENSG00000152315 (K2P13.1) | ENSG00000186795 (K2P18.1) |
| Activators | – | Halothane (not TRAAK), riluzole, stretch, heat, arachidonic acid, acid pHi | Halothane, alkaline pHo (K2P3.1) | Alkaline pHO | – | – |
| Inhibitors | Acid pHi | – | Anandamide (K2P3.1, K2P9.1) ruthenium red (K2P9.1) acid pHO | – | Halothane | Arachidonic acid |
| Functional characteristic | Background current | Background current | Background current | Background current | Background current | Background current |
The K2P7.1, K2P15.1 and K2P12.1 subtypes, when expressed in isolation, are non-functional. All 4TM channels are insensitive to the classical potassium channel blockers TEA and 4-AP, but are blocked to varying degrees by Ba2+ ions.
The 6TM family of K channels
The 6TM family of K channels comprises the voltage-gated KV subfamilies, the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Ca2+-activated Slo subfamily (actually with 7TM) and the Ca2+-activated SK subfamily. As for the 2TM family, the pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. KV1.1 with KV1.2; KCNQ2 with KCNQ3).
| Subfamily group | KV1.x | KV2.x | KV3.x | KV4.x |
|---|---|---|---|---|
| Subtypes | KV1.1–KV1.8 | KV2.1–2.2 | KV3.1–3.4 | KV4.1–4.3 |
| Shaker-related | Shab-related | Shal-related | Shaw-related | |
| Ensembl ID | ENSG00000111262 (KV1.1) | ENSG00000158445 (KV2.1) | ENSG00000129159 (KV3.1) | ENSG00000102057 (KV4.1) |
| Inhibitors | TEA potent (1.1), TEA moderate (1.3, 1.6), 4-AP potent (1.4), α-dendrotoxin (1.1, 1.2, 1.6), margatoxin (1.1, 1.2, 1.3), noxiustoxin (1.2, 1.3) | TEA moderate | TEA potent, 4-AP potent (3.1, 3.2), BDS-1 (3.4) | – |
| Functional characteristics | KV (1.1–1.3, 1.5–1.8), KA (1.4) | KV (2.1) | KV (3.1, 3.2), KA (3.3, 3.4) | KA |
| Associated subunits | KVβ1, KVβ2 | KV5.1, KV6.1–6.3, KV8.1, KV9.1–9.3 | MiRP2 (KV3.4) | KChIP, KChAP |
| Subfamily group | KV7.x (‘KCNQ’) | KV10.x, KV11.x, KV12.x (‘EAG’) | KCa1.x, KCa4.x, KCa5.x (‘Slo’) | KCa2.x, KCa3.x (‘SK’) |
|---|---|---|---|---|
| Subtypes | KV7.1–7.5 (KCNQ1-5) | KV10.1–10.2 (eag1–2) | KCa1.1, KCa4.1–4.2, KCa5.1 | KCa2.1–2.3 (SK1–SK3) |
| KV11.1–11.3 (erg1-3, herg 1–3) | Slo (BK), Slack, Slick | KCa3.1 (SK4, IK) | ||
| KV12.1–12.3 (elk1-3) | ||||
| Ensembl ID | ENSG00000053918 (KV7.1) | ENSG00000143473 (KV10.1) | ENSG00000156113 (KCa1.1) | ENSG00000105642 (KCa2.1) |
| Activators | Retigabine (KV7.2,–5) | – | NS004, NS1619 | – |
| Inhibitors | TEA (KV7.2, 7.4), XE991 (KV7.1, 7.2, 7.4, 7.5), linopirdine | E-4031 (KV11.1), astemizole (KV11.1), terfenadine (KV11.1) | TEA, charybdotoxin, iberiotoxin | Charybdotoxin (KCa3.1), apamin (KCa2.1–2.3) |
| Functional characteristic | KV7.1 – cardiac IKSKV7.2/7.3–M current | KV11.1 – cardiac IKR | Maxi KCa KNa (slack & slick) | SKCa (KCa2.1–2.3) IKCa (KCa3.1) |
| Associated subunits | minK, MiRP2 (KV.7.1) | minK, MiRP1 (erg1) | – | – |
Glossary
Abbreviations:
- 4-AP
4-aminopyridine
- BDS-1
blood depressing substance 1
- E-4031
1-(2-(6-methyl-2-pyridyl)ethyl)-4-(4-methylsulphonyl aminobenzoyl)piperidine
- NS004
1-(2-hydroxy-5-chlorophenyl)-5-trifluromethyl-2-benzimidazolone
- NS1619
1-(2′-hydroxy-5′-trifluromethylphenyl)-5-trifluro-methyl-2(3H)benzimidazolone
- PIP2
phosphatidylinositol 4,5, bisphosphate
- TEA
tetraethylammonium
- XE991
10,10-bis(4-pyridinylmethyl)-9(10H)-anthracene
Further Reading
Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J (1998). Toward understanding the assembly and structure of KATP channels. Physiol Rev78: 227–245.
Ahern CA, Kobertz WR (2009). Chemical tools for K+ channel biology. Biochemistry48: 517–526.
Ashcroft FM, Gribble FM (1998). Correlating structure and function in ATP-sensitive K+ channels. Trends Neurosci21: 288–294.
Bauer CK, Schwartz JR (2001). Physiology of EAG channels. J Membr Biol182: 1–15.
Bayliss DA, Barrett PQ (2008). Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol Sci29: 566–575.
Bean BP (2007). The action potential in mammalian central neurons. Nat Rev Neurosci8: 451–465.
Bezanilla F (2000). The voltage sensor in voltage-dependent ion channels. Physiol Rev80: 555–592.
Dalby-Brown W, Hansen HH, Korsgaard MP, Mirza N, Olesen SP (2006). Kv7 channels: function, pharmacology and channel modulators. Curr Top Med Chem6: 999–1023.
Goldstein SAN, Bockenhauer D, O'Kelly I, Zilberberg N (2001). Potassium leak channels and the KCNK family of two-P domain subunits. Nat Rev Neurosci2: 175–184.
Goldstein SAN, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S (2005). International Union of Pharmacology. LV. Nomenclature and molecular relationships of Two-P potassium channels. Pharmacol Rev57: 527–540.
Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA et al. (2005). International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev57: 473–508.
Hancox JC, McPate MJ, El Harchi A, Zhang YH (2008). The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther119: 118–132.
Hansen JB (2006). Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives. Curr Med Chem13: 26–376.
Honore E (2007). The neuronal background K2P channels: focus on TREK1. Nature Rev Neurosci8: 251–261.
Jenkinson DH (2006). Potassium channels – multiplicity and challenges. Br J Pharmacol147 (Suppl. 1): S63–S71.
Judge SI, Bever CT Jr (2006). Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther111: 224–259.
Kaczorowski GJ, Garcia ML (1999). Pharmacology of voltage-gated and calcium-activated potassium channels. Curr Opin Chem Biol3: 448–458.
Kobayashi T, Ikeda K (2006). G protein-activated inwardly-rectifying potassium channels as potential therapeutic targets. Curr Pharm Des12: 4513–4523.
Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y et al. (2005). International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol Rev57: 509–526.
Lawson K, McKay NG (2006). Modulation of potassium channels as a therapeutic approach. Curr Pharm Des12: 459–470.
Lesage F (2003). Pharmacology of neuronal background potassium channels. Neuropharmacology44: 1–7.
Lewis RJ, Garcia ML (2003). Therapeutic potential of venom peptides. Nat Rev Drug Discov2: 790–802.
Mannhold R (2006). Structure-activity relationships of KATP channel openers. Curr Top Med Chem6: 1031–1047.
Mathie A, Veale EL (2007). Therapeutic potential of neuronal two pore domain potassium channel modulators. Curr Opin Invest Drugs8: 555–562.
Miller C (2003). A charged view of voltage-gated ion channels. Nat Struct Biol10: 422–424.
Nardi A, Olesen SP (2008). BK channel modulators: a comprehensive review. Curr Med Chem15: 1126–1146.
Nichols CG, Lopatin AN (1997). Inwardly rectifying potassium channels. Annu Rev Physiol59: 171–191.
O'Connell AD, Morton MJ, Hunter M (2002). Two-pore domain K+ channels – molecular sensors. Biochim Biophys Acta – Biomembranes1566: 152–161.
Reimann F, Ashcroft FM (1999). Inwardly rectifying potassium channels. Curr Opin Cell Biol11: 503–508.
Robbins J (2001). KCNQ potassium channels: physiology, pathophysiology and pharmacology. Pharmacol Ther90: 1–19.
Salkoff L, Butler A, Ferreira G, Santi C, Wei A (2006). High-conductance potassium channels of the SLO family. Nature Rev Neurosci7: 921–931.
Sanguinetti MC (2000). Maximal function of minimal K+ channel subunits. Trends Pharmacol Sci21: 199–201.
Seino S, Miki T (2003). Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol81: 133–176.
Stanfield PR, Nakajima S, Nakajima Y (2002). Constitutively active and G-protein coupled inward rectifier K+ channels: Kir2.0 and Kir3.0. Rev Physiol Biochem Pharmacol145: 47–179.
Stocker M (2004). Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci5: 758–770.
Trimmer JS, Rhodes KJ (2004). Localisation of voltage-gated ion channels in mammalian brain. Annu Rev Physiol66: 477–519.
Wang H, Tang Y, Wang L, Long CL, Zhang YL (2007). ATP-sensitive potassium channel openers and 2,3-dimethyl-2-butylamine derivatives. Curr Med Chem14: 133–155.
Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H (2005). International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated channels. Pharmacol Rev57: 463–472.
Wickenden AD, McNaughton-Smith G (2009). Kv7 channels as targets for the treatment of pain. Curr Pharm Des15: 1773–1798.
Witchel HJ (2007). The hERG potassium channel as a therapeutic target. Expert Opin Ther Targets11: 321–336.
Yellen G (2002). The voltage-gated potassium channels and their relatives. Nature419: 35–42.
Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.