Chronic and acute regulation of Na+/Cl- -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems.
Na+/Cl- -dependent neurotransmitter transporters, which constitute a gene superfamily, are crucial for limiting neurotransmitter activity. Thus, it is critical to understand their regulation. This review focuses primarily on the norepinephrine transporter, the dopamine transporter, the serotonin transporter, and the gamma-aminobutyric acid transporter GAT1. Chronic administration of drugs that alter neurotransmitter release or inhibit transporter activity can produce persistent compensatory changes in brain transporter number and activity. However, regulation has not been universally observed. Transient alterations in norepinephrine transporter, dopamine transporter, serotonin transporter, and GAT1 function and/or number occur in response to more acute manipulations, including membrane potential changes, substrate exposure, ethanol exposure, and presynaptic receptor activation/inhibition. In many cases, acute regulation has been shown to result from a rapid redistribution of the transporter between the cell surface and intracellular sites. Second messenger systems involved in this rapid regulation include protein kinases and phosphatases, of which protein kinase C has been the best characterized. These signaling systems share the common characteristic of altering maximal transport velocity and/or cell surface expression, consistent with regulation of transporter trafficking. Although less well characterized, arachidonic acid, reactive oxygen species, and nitric oxide also alter transporter function. In addition to post-translational modifications, cytoskeleton interactions and transporter oligomerization regulate transporter activity and trafficking. Furthermore, promoter regions involved in transporter transcriptional regulation have begun to be identified. Together, these findings suggest that Na+/Cl- -dependent neurotransmitter transporters are regulated both long-term and in a more dynamic manner, thereby providing several distinct mechanisms for altering synaptic neurotransmitter concentrations and neurotransmission.
Zahniser
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Department of Pharmacology, C-236, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. nancy.zahniser@uchsc.edu
Doolen
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D000818:Animals; D017660:Autoreceptors / Q000502:physiology; D001692:Biological Transport; D002352:Carrier Proteins / Q000187:drug effects / Q000502:physiology*; D002713:Chlorine / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000502:physiology; D027981:Symporters / Q000187:drug effects / Q000502:physiology*
D017660:Autoreceptors; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D002713:Chlorine; D012964:Sodium