Amine Transporters


Amine transporters in plasma membranes mediate the transport of dopamine, (nor)adrenaline ((nor)epinephrine) and serotonin. These transporters are members of the larger Na+‐ and Cl‐dependent neurotransmitter transporters.

Keywords: dopamine; noradrenaline; norepinephrine; serotonin; sodium; chloride

Figure 1.

Amine transporters in plasma membranes and in membranes of storage vesicles. The amine transporter in the plasma membrane transports amine (A) from the extracellular space into the cytoplasm, with cotransport of Na+ and Cl. This uptake is driven by the inwardly directed Na+ gradient and outwardly directed K+ gradient, maintained by Na+/K+ adenosine triphosphatase (ATPase). Uptake of dopamine and noradrenaline, but not of serotonin, is also promoted by the membrane potential, negative inside. In contrast, the vesicular amine transporter (VAT) takes up A with countertransport of H+, and the high intravesicular H+ concentration is maintained by the ATP‐dependent H+ pump or H+‐transporting ATPase (HT ATPase). On the postsynaptic side, an amine receptor is depicted coupled to G protein subunits.

Figure 2.

Proposed topology of plasma membrane amine transporters. The large extracellular loop between transmembrane domains 3 and 4 have two to four consensus sites for glycosylation (ψ), whereas consensus sites for phosphorylation by PKA (A), PKC (C) or Ca2+–calmodulin‐dependent kinase II (KII) are found on the amino and carboxy tails as well as on the second intracellular loop.

Figure 3.

Translocation cycle. Starting at the lower left and continuing counterclockwise, the transporter facing outward binds Na+, Cl and amine (A). A conformational change occurs bringing the transporter in a form facing inward (top right‐hand corner) allowing the dissociation of Na+, Cl and A. The empty, inward‐facing, transporter undergoes the reorientation step (top left to bottom left), which in the case of the serotonin transporter is promoted by K+. The transporter is now ready for a new translocation cycle.



Berfield JL, Wang LC and Reith MEA (1999) Which form of dopamine is the substrate for the human dopamine transporter: the cationic or the uncharged species?. Journal of Biological Chemistry 274: 4876–4882.

Chen N and Reith MEA (2002) Structure–function relationships for biogenic amine neurotransmitter transporters. In: Reith MEA (ed.) Neurotransmitter Transporters: Structure, Function, and Regulation, 2nd edn, pp. 53–109. Totowa, NJ: Humana Press.

Chen JG, Sachpatzidis A and Rudnick G (1997) The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding. Journal of Biological Chemistry 272: 28321–28327.

Chen N, Sun L and Reith MEA (2002) Cationic interactions at the human dopamine transporter reveal binding conformations for dopamine distinguishable from those for the cocaine analog 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane. Journal of Neurochemistry 81: 1383–1393.

Ferrer JV and Javitch JA (1998) Cocaine alters the accessibility of endogenous cysteines in putative extracellular and intracellular loops of the human dopamine transporter. Proceedings of the National Academy of Sciences of the USA 95: 9238–9243.

Giros B, Jaber M, Jones SR, Wightman RM and Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379: 606–612.

Gulley JM and Zahniser NR (2003) Rapid regulation of dopamine transporter function by substrates, blockers, and presynaptic receptor ligands. European Journal of Pharmacology 479: 139–152.

Hahn MK and Blakely RD (2002) Gene organization and polymorphisms of monoamine transporters: relationship to psychiatric and other complex diseases. In: Reith MEA (ed.) Neurotransmitter Transporters, Structure, Function, and Regulation, 2nd edn, pp. 111–170. Totowa, NJ: Humana Press.

Khoshbouei H, Wang H, Lechleiter JD, Javitch JA and Galli A (2003) Amphetamine‐induced dopamine efflux. A voltage‐sensitive and intracellular Na+ ‐dependent mechanism. Journal of Biological Chemistry 278: 12070–12070.

Kilic F and Rudnick G (2000) Oligomerization of the serotonin transporter and its functional consequences. Proceedings of the National Academy of Sciences of the USA 97: 3106–3111.

Langer SZ, Moret C, Raisman R, Dubocovich ML and Briley M (1980) High‐affinity [3H]imipramine binding in rat hypothalamus: association with uptake of serotonin but not of norepinephrine. Science 210: 1133–1135.

Li LB, Chen N, Ramamoorthy R, Chi L, Cui X‐N, Wang LC and Reith MEW (2004) The role of N‐glycosylation in function and trafficking of the human dopamine transporter. Journal of Biological Chemistry 279: 21012–21020.

Li LB, Cui XN and Reith MEA (2002) Is Na+ required for the binding of dopamine, amphetamine, tyramine and octopamine to the human dopamine transporter?. Naunyn‐Schmiedebergs Archives Pharmacology 365: 303–311.

Melikian HE, Ramamoorthy S, Tate CG and Blakely RD (1996) Inability to N‐glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition. Molecular Pharmacology 50: 266–276.

Pacholczyk T, Blakely RD and Amara SG (1991) Expression cloning of a cocaine‐ and antidepressant‐sensitive human noradrenaline transporter. Nature 350: 350–354.

Ritz MC, Lamb RJ, Goldberg SR and Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self‐administration of cocaine. Science 237: 1219–1223.

Rocha BA, Fumagalli F, Gainetdinov RR, et al. (1998) Cocaine self‐administration in dopamine‐transporter knockout mice. Nature Neuroscience 1: 132–137.

Sitte HH and Freissmuth M (2003) Oligomer formation by Na+‐Cl− coupled neurotransmitter transporters. European Journal of Pharmacology 479: 229–236.

Snyder SH and Coyle JT (1969) Regional differences in H3‐norepinephrine and H3‐dopamine uptake into rat brain homogenates. Journal of Pharmacology and Experimental Therapeutics 165: 78–86.

Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP and Amara SG (1997) Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. Journal of Neuroscience 17: 960–974.

Torres GE, Carneiro A, Seaman K, et al. (2003) Oligomerization and trafficking of human dopamine transporter: mutation analysis identifies domains important for the functional expression. Journal of Biological Chemistry 278: 2731–2739.

Further Reading

Amara SA (ed.) (1998) Neurotransmitter transporters. Methods in Enzymology 296: 1–730.

Cao Y, Li M, Mager S and Lester HA (1998) Amino acid residues that control pH modulation of transport‐associated current in mammalian serotonin transporters. Journal of Neuroscience 18: 7739–7749.

Lin Z, Wang W, Kopatjic T, Revay RS and Uhl GR (1999) Dopamine transporter: transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition. Molecular Pharmacology 56: 434–447.

Lin Z, Wang W and Uhl GR (2000) Dopamine transporter tryptophan mutants highlight candidate dopamine‐ and cocaine‐selective domains. Molecular Pharmacology 58: 1581–1592.

Reith MEA (ed.) (2002) Neurotransmitter Transporters: Structure, Function and Regulation, 2nd edn. Totowa, NJ: Humana Press.

Reith MEA (guest ed.) (2003) Transporters as targets for drugs and endogenous compounds. European Journal of Pharmacology, (Special Issue) Vol. 479, Nos. 1–3.

Robinson MB (2002) Regulated trafficking of neurotransmitter transporters: common notes but different melodies. Journal of Neurochemistry 80: 1–11.

Roubert C, Cox PJ, Brüss M, et al. (2001) Determination of residues in the norepinephrine transporter that are critical for tricyclic antidepressant affinity. Journal of Biological Chemistry 276: 8254–8260.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Zhen, Juan, and Reith, Maarten EA(Sep 2005) Amine Transporters. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0004091]