Monoamine

Overview: Plasma membrane located monoamine transporters (provisional nomenclature) transport the hormone/transmitters adrenaline, noradrenaline, dopamine and 5-hydroxytryptamine, and are members of the solute carrier family 6 (SLC6) of sodium- and chloride-dependent neurotransmitter transporters that includes the GABA and glycine transporters (Chen et al., 2004). The members of this superfamily share a structural motif of 12 putative transmembrane segments (Palacín et al., 1998). A high-resolution structure of a bacterial homologue of these transporters has been reported recently (Yamashita et al., 2005).

Nomenclature	DAT	NET	SERT
Systematic name	SLC6A3	SLC6A2	SLC6A4
Other names	DAT1	NAT1	5-HTT, SERT1
Ensembl ID	ENSG00000142319	ENSG00000103546	ENSG00000108576
Endogenous substrates	Dopamine, adrenaline, noradrenaline	Noradrenaline, adrenaline, dopamine	5-HT
Synthetic substrates	Amphetamine, methamphetamine, MPP+	Amphetamine, methamphetamine, MPP+	p-Chloroamphetamine, MDMA
Selective inhibitors	Mazindol (8.0), WIN35428 (7.9), GBR12935 (7.6)	Mazindol (8.9), nisoxetine (8.4), nomifensine (8.1)	Paroxetine (9.6, Tatsumi et al., 1997), sertraline (9.1), fluoxetine (8.5, Tatsumi et al., 1997)
Probes	[3H]-GBR12935 (3 nM, Pristupa et al., 1994), [3H]-WIN35428 (10 nM, Pristupa et al., 1994)	[3H]-Mazindol (0.5 nM), [3H]-nisoxetine (4 nM)	[3H]-Paroxetine (0.2 nM), [3H]-citalopram (5 nM)
Predicted stoichiometry	1 Dopamine:1–2 Na+:1 Cl- (Gu et al., 1994)	1 Noradrenaline: 1 Na+:1 Cl- (Gu et al., 1996)	1 5-HT:1 Na+:1 Cl- (in), +1 K+ (out) (Talvenheimo et al., 1983)

[¹²⁵I]-RTI55 labels all three transporters 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 (Singh et al., 2007).

Glossary

Abbreviations:

GBR12935

1-(2-[diphenylmethoxy]ethyl)-4-(3-phenylpropyl)piperazine

MDMA

3,4-methylenedioxymethamphetamine

MPP⁺

1-methyl-4-phenylpyridinium

RTI55

2β-carbomethoxy-3β-(4-iodophenyl) tropane (also known as β-CIT)

WIN35428

2β-carboxymethy-3β-(4-fluorophenyl)tropane (also known as β-CFT)

Further Reading

Chen NH, Reith ME, Quick MW (2004). Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch447: 519–531.

Foster JD, Cervinski MA, Gorentla BK, Vaughan RA (2006). Regulation of the dopamine transporter by phosphorylation. Handb Exp Pharmacol175: 197–214.

Mazei-Robinson MS, Blakely RD (2006). ADHD and the dopamine transporter: are there reasons to pay attention? Handb Exp Pharmacol175: 373–415.

Millan MJ (2006). Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther110: 135–370.

Moltzen EK, Bang-Andersen B (2006). Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century–a medicinal chemistry survey. Curr Top Med Chem6: 1801–1823.

Palacín M, Estévez R, Bertran J, Zorzano A (1998). Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev78: 969–1054.

Runyon SP, Carroll FI (2006). Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem6: 1825–1843.

Torres GE, Gainetdinov RR, Caron MG (2003). Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci4: 13–25.

Williams JM, Galli A (2006). The dopamine transporter: a vigilant border control for psychostimulant action. Handb Exp Pharmacol175: 215–232.