Amine Transporters


Amine transporters in plasma membranes of nerve cells mediate the transport of dopamine, (nor)adrenaline and serotonin. These transporters are members of the larger Na+‐ and Cl‐dependent neurotransmitter transporter family. All three transporters have been cloned, and the bacterial leucine transporter was the first prototypical structure available; this was followed by crystals of the drosophila dopamine transporter and the human serotonin transporter. Amine transporters are implicated in psychiatric disorders, such as attention‐deficit/hyperactivity disorder, schizophrenia, Parkinson disease, suicidal and aggressive‐impulsive behaviour, and are involved in affective disorders including depression. Amine transporters are important targets for psychostimulant drugs as well as antidepressants.

Key Concepts

  • Amine transporters in plasma membranes of nerve cells mediate the transport of dopamine, noradrenaline, adrenaline and serotonin through cotransport with Na+ towards the cytosol where the Na+ concentration is low.
  • Amine uptake is best described by the alternating access model; accordingly, the transporter protein moves back and forth between outward‐ and inward‐facing conformations.
  • Amine transporters are organised in multimeric structures, that is, oligomers consisting of varying numbers of protomers. How oligomerisation affects the function of each protomer is not fully understood.
  • In addition to a primary central binding site for substrate and drugs, amine transporters have an extracellular vestibule, accommodating with appreciable flexibility varying small‐molecule allosteric ligands.
  • Transporter polymorphisms and variants have been associated with increased risk for psychiatric diseases; a number of DAT variants, one‐point mutations, are known to cause parkinsonian symptoms starting at infancy in a hereditary recessive fashion.
  • In addition to allosteric modulators, atypical inhibitors and releasers targeting amine transporters are subject of intense research.

Keywords: dopamine; noradrenaline; serotonin; sodium; chloride; glycosylation; cocaine; amphetamine; antidepressants

Figure 1. Amine transporters in plasma membranes and in membranes of storage vesicles. The extrasynaptic 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 extrasynaptic amine receptor is depicted coupled to G protein subunits. Components relative to each other are not drawn on an absolute scale, and for a more detailed depiction of amine volume transmission see Rice and Cragg , Figure 7. Zhen and Reith . Reproduced with permission of John Wiley & Sons.
Figure 2. Two‐dimensional topology of hDAT computed from LeuT structure (Schmitt et al., ). Twelve transmembrane domains are shown with helically unwound regions in first and sixth transmembrane domain; extra‐ and intra‐cellular loops include helical portions (e2, e3, e4a, e4b and i1, i5, respectively) (Yamashita et al., ). Upstream from e2 the three N‐linked glycosylation sites are shown. In the 3‐dimensional structure, sodium ions (purple balls) interact not only with residues of transmembrane domains 1, 6 and 8 but also 7 (Yamashita et al., ). Bound chloride ion is indicated by the green ball (Coleman et al., ). A DA molecule (not on scale) is depicted between the helically unwound regions of transmembrane domains 1 and 6. DTDS‐linked mutated residues are shown in red (with arrows indicating their positions).
Figure 3. Structure of SERT viewed parallel to the membrane as reported by Coleman et al. . The (S)‐citalopram molecules at the central and allosteric site are shown as sticks in dark green and cyan, respectively. Sodium ions are shown in spheres in salmon. Cholesteryl hemisuccinate (CHS) and N‐acetylglucosamine (NAG) are shown as sticks. Coleman et al. . Reproduced with permission of Springer Nature.
Figure 4. Translocation of substrate by an amine transporter as depicted through computational models of hDAT based on LeuT, previously reported by Schmitt et al. . (a) DAT models demonstrating the configuration of the extra‐ and intracellular gating networks and the substrate permeation pore in the open‐to‐out, occluded and open‐to‐in conformational states. Formation and disruption of salt bridges and π‐cation interactions between residues in the two gating networks (labelled and rendered as highlighted yellow sticks) underlies the “alternating access” translocation mechanism. As the gates are reciprocally opened and closed, the respective periplasmic and cytoplasmic substrate permeation pores (rendered as a translucent molecular surface, with hydrophobic regions in green, polar regions in purple and solvent‐exposed regions in red) grow significantly, facilitating water infiltration and diffusion of the substrate. (b) An illustration of the putative substrate translocation cycle for the DAT protein. In the absence of bound ions or ligands, the transporter protein exists in dynamic flux between outward‐ and inward‐facing states (left, middle and top). Binding of Na+ at the S1 site (right‐hand side) stabilises a fully outward‐facing conformation with an open extracellular gate, primed to bind substrate molecules. Substrate binding at the S1 site induces closure of the extracellular gate, establishing an occluded conformation (closed‐to‐out). Perhaps with the interaction of a second substrate molecule with the S2 site, an opening occurs of the intracellular gating network, giving rise to a fully inward‐facing (open‐to‐in) conformation (bottom, middle) capable of releasing the S1‐bound substrate and ions; in the case of the hSERT structure (Figure ) a simultaneous interaction of two substrate molecules has been found. Schmitt et al. . Reproduced with permission of American Society for Pharmacology and Experimental Therapeutics.


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Further Reading

Anderluh A, Klotzsch E, Reismann AW, et al. (2014) Single molecule analysis reveals coexistence of stable serotonin transporter monomers and oligomers in the live cell plasma membrane. The Journal of Biological Chemistry 289: 4387–4394.

Anderluh A, Hofmaier T, Klotzsch E, et al. (2017) Direct PIP2 binding mediates stable oligomer formation of the serotonin transporter. Nature Communications 8: 14089.

Bolland DE, Moritz AE, Stanislowski DJ, Vaughan RA and Foster JD (2019) Palmitoylation by multiple DHHC enzymes enhances dopamine transporter function and stability. ACS Chemical Neuroscience 10: 2707–2717.

Hasenhuetl PS, Bhat S, Freissmuth M and Sandtner W (2019) Functional selectivity and partial efficacy at the monoamine transporters: a unified model of allosteric modulation and amphetamine‐induced substrate release. Molecular Pharmacology 95: 303–312.

Karam CS and Javitch JA (2018) Phosphorylation of the amino terminus of the dopamine transporter: regulatory mechanisms and implications for amphetamine action. Advances in Pharmacology 82: 205–234.

Rives ML, Javitch JA and Wickenden AD (2017) Potentiating SLC transporter activity: emerging drug discovery opportunities. Biochemical Pharmacology 135: 1–11.

Yang JW, Larson G, Konrad L, et al. (2019) Dephosphorylation of human dopamine transporter at threonine 48 by protein phosphatase PP1/2A up‐regulates transport velocity. The Journal of Biological Chemistry 294: 3419–3431.

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Reith, Maarten EA(Jan 2020) Amine Transporters. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000009.pub3]