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Physiology and Pharmacology of Neurotransmitter Transporters

Nadia Ayala‐Lopez, Stephanie W. Watts

10.1002/cphy.c200035

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

Regulation of the ability of a neurotransmitter [our focus: serotonin, norepinephrine, dopamine, acetylcholine, glycine, and gamma‐aminobutyric acid (GABA)] to reach its receptor targets is regulated in part by controlling the access the neurotransmitter has to receptors. Transporters, located at both the cellular plasma membrane and in subcellular vesicles, carry a myriad of responsibilities that include enabling neurotransmitter release and controlling uptake of neurotransmitter back into a cell or vesicle. Driven largely by electrochemical gradients, these transporters move neurotransmitters. The regulation of the transporters themselves through changes in expression and/or posttranslational modification allows for fine‐tuning of this system. Transporters have been best recognized as targets for psychoactive stimulants and remain a mainstay target of primarily central nervous system (CNS) acting drugs for treatment of debilitating diseases such as depression and anxiety. Studies reveal, however, that transporters are found and functional in tissues outside the CNS (gastrointestinal and cardiovascular tissues, for example). The importance of neurotransmitter transporters is underscored with discoveries that dysfunction of transporters can cause life‐changing disease. This article provides a high‐level review of major classes of both plasma membrane transporters and vesicular transporters. © 2021 American Physiological Society. Compr Physiol 11:2279‐2295, 2021.

Figure 1. Figure 1. Rendition of plasma membrane transporters (A; blue) compared to vesicular transporters (B; purple) and the associated cellular machinery that drive electrical and concentration gradients that enable transport. (C) Depiction comparing and contrasting uniport, symport, and antiport transport.
Figure 2. Figure 2. Dendrograms of plasma membrane (A) Reused, with permission, from Focke PJ, et al., 2013 29. and vesicular (B) transporters. Reused, with permission, from Lawal HO and Krantz DE, 2013 49.
Figure 3. Figure 3. NET transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Aggarwal S and Mortensen OV, 2017 1 and Schroeder C and Jordan J, 2012 84.
Figure 4. Figure 4. SERT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Rudnick G and Sandtner W, 2019 80.
Figure 5. Figure 5. DAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Aggarwal S and Mortensen OV, 2017 1 and Lohr KM, et al., 2017 54.
Figure 6. Figure 6. GAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Scimemi A, 2014 85.
Figure 7. Figure 7. GlyT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Aragon C and Lopez‐Corcuera B, 2003 5.
Figure 8. Figure 8. OCT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Koepsell H, 2020 44.
Figure 9. Figure 9. EAAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Malik AR and Willnow TE, 2019 55 and Rose CR, et al., 2018 77.
Figure 10. Figure 10. PAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Boll M, et al., 2004 13, Fan SJ and Goberdhan DCI, 2018 27 and Thwaites DT and Anderson CMH, 2011 89.
Figure 11. Figure 11. VAChT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Lawal HO and Krantz DE, 2013 49 and Prado VF, et al., 2013 70.
Figure 12. Figure 12. VMAT transport. The table shares genetic, substrate, inhibitor, physiological and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from German CL, et al., 2015 33 and Yaffe D, et al., 2018 96.
Figure 13. Figure 13. VGLUT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Liguz‐Lecznar M and Skangiel‐Kramska J, 2007 51.
Figure 14. Figure 14. VIAAT/VGAY transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Gasnier B, 2004 32.
Figure 15. Figure 15. VNUT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Hasuzawa N, et al., 2020 36, Miras‐Portugal MT, et al., 2019 61 and Moriyama Y, et al., 2017 62.


Figure 1. Rendition of plasma membrane transporters (A; blue) compared to vesicular transporters (B; purple) and the associated cellular machinery that drive electrical and concentration gradients that enable transport. (C) Depiction comparing and contrasting uniport, symport, and antiport transport.


Figure 2. Dendrograms of plasma membrane (A) Reused, with permission, from Focke PJ, et al., 2013 29. and vesicular (B) transporters. Reused, with permission, from Lawal HO and Krantz DE, 2013 49.


Figure 3. NET transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Aggarwal S and Mortensen OV, 2017 1 and Schroeder C and Jordan J, 2012 84.


Figure 4. SERT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Rudnick G and Sandtner W, 2019 80.


Figure 5. DAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Aggarwal S and Mortensen OV, 2017 1 and Lohr KM, et al., 2017 54.


Figure 6. GAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Scimemi A, 2014 85.


Figure 7. GlyT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Aragon C and Lopez‐Corcuera B, 2003 5.


Figure 8. OCT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Koepsell H, 2020 44.


Figure 9. EAAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Malik AR and Willnow TE, 2019 55 and Rose CR, et al., 2018 77.


Figure 10. PAT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Boll M, et al., 2004 13, Fan SJ and Goberdhan DCI, 2018 27 and Thwaites DT and Anderson CMH, 2011 89.


Figure 11. VAChT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Lawal HO and Krantz DE, 2013 49 and Prado VF, et al., 2013 70.


Figure 12. VMAT transport. The table shares genetic, substrate, inhibitor, physiological and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from German CL, et al., 2015 33 and Yaffe D, et al., 2018 96.


Figure 13. VGLUT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Liguz‐Lecznar M and Skangiel‐Kramska J, 2007 51.


Figure 14. VIAAT/VGAY transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Gasnier B, 2004 32.


Figure 15. VNUT transport. The table shares genetic, substrate, inhibitor, physiological, and functional information while the cartoon at the right depicts membrane transport. Adapted, with permission, from Hasuzawa N, et al., 2020 36, Miras‐Portugal MT, et al., 2019 61 and Moriyama Y, et al., 2017 62.
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Article Title: Physiology and Pharmacology of Neurotransmitter Transporters
 

How to Cite

Nadia Ayala‐Lopez, Stephanie W. Watts. Physiology and Pharmacology of Neurotransmitter Transporters. Compr Physiol 2021, 11: 2279-2295. doi: 10.1002/cphy.c200035