Neurotransmitter transporter
Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.[1]
Vesicular transporters move neurotransmitters into synaptic vesicles, regulating the concentrations of substances within them.[2] Vesicular transporters rely on a proton gradient created by the hydrolysis of adenosine triphosphate (ATP) in order to carry out their work: vesicle ATPase hydrolyzes ATP, causing protons to be pumped into the Synaptic vesicles and creating a proton gradient. Then the efflux of protons from the vesicle provides the energy to bring the neurotransmitter into the vesicle.[3]
Neurotransmitter transporters frequently use electrochemical gradients that exist across cell membranes to carry out their work. For example, some transporters use energy obtained by the cotransport of Na+ in order to move glutamate across membranes.
Normally, transporters in the synaptic membrane serve to remove neurotransmitters from the synaptic cleft and prevent their action or bring it to an end. However, on occasion transporters can work in reverse, transporting neurotransmitters into the synapse, allowing these neurotransmitters to bind to their receptors and exert their effect. This "nonvesicular release" of neurotransmitters is used by some cells, such as amacrine cells in the retina, as a normal form of neurotransmitter release.[4]
Types
Specific types of neurotransmitter transporters include the following:
- Glutamate/aspartate transporters, including:
- Excitatory amino acid transporter 1 (EAAT1)
- Excitatory amino acid transporter 2 (EAAT2)
- Excitatory amino acid transporter 3 (EAAT3)
- Excitatory amino acid transporter 4 (EAAT4)
- Excitatory amino acid transporter 5 (EAAT5)
- Vesicular glutamate transporter 1 (VGLUT1)
- Vesicular glutamate transporter 2 (VGLUT2)
- Vesicular glutamate transporter 3 (VGLUT3)
- GABA transporters, including:
- GABA transporter type 1 (GAT1)
- GABA transporter type 2 (GAT2)
- GABA transporter type 3 (GAT3)
- Betaine transporter (BGT1)
- Vesicular GABA transporter (VGAT)
- Glycine transporters, including:
- Glycine transporter type 1 (GlyT1)
- Glycine transporter type 2 (GlyT2)
- Monoamine transporters, including:
- Dopamine transporter (DAT)
- Norepinephrine transporter (NET)
- Serotonin transporter (SERT)
- Vesicular monoamine transporter 1 (VMAT1)
- Vesicular monoamine transporter 2 (VMAT2)
- Adenosine transporters, including:
Note that there is no plasmalemmal acetylcholine transporter, as acetylcholine is terminated via rapid metabolism into choline by cholinesterase enzymes, and choline is subsequently transported back into the cell and reconverted into acetylcholine.
Transporters associated with histamine and the endocannabinoids have not yet been identified.
Clinical significance
Antidepressants such as SSRIs, SNRIs and TCAs suppress the activity of serotonin and/or norepinephrine transporters, preventing the reuptake of targeted neurotransmitters from the synaptic cleft.
Psychostimulants like cocaine, amphetamines, and methylphenidate act by inhibiting and/or reversing the dopamine and norepinephrine transporters. Some dissociatives like phencyclidine and ketamine are also dopamine transporter blockers.
Tiagabine, a drug used as an anticonvulsant, acts by inhibiting the GABA transporter 1.
References
- ^ Iversen L (2000). "Neurotransmitter transporters: fruitful targets for CNS drug discovery". Mol. Psychiatry. 5 (4): 357–62. doi:10.1038/sj.mp.4000728. PMID 10889545.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Johnson J, Tian N, Caywood MS, Reimer RJ, Edwards RH, Copenhagen DR (2003). "Vesicular neurotransmitter transporter expression in developing postnatal rodent retina: GABA and glycine precede glutamate". J. Neurosci. 23 (2): 518–29. PMID 12533612.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Kandel ER, Schwartz JH, Jessell TM (2000). Principles of neural science (4th ed.). New York: McGraw-Hill. p. 287. ISBN 0-8385-7701-6.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Kandel ER, Schwartz JH, Jessell TM (2000). Principles of neural science (4th ed.). New York: McGraw-Hill. p. 295. ISBN 0-8385-7701-6.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Weihe E, Tao-Cheng JH, Schäfer MK, Erickson JD, Eiden LE (1996). "Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles". Proc Natl Acad Sci USA. 93 (8): 3547–52. doi:10.1073/pnas.93.8.3547. PMC 39647. PMID 8622973.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
External links
- Neurotransmitter+Transporters at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Clearing Your Mind of Neurotransmitters: Functional Impact of Neurotransmitter Transporter Gene Variants - a videocast of the lecture by Randy Blakely, Ph.D., Vanderbilt University. Part of NIH Neuroscience Seminar series. 450 Mb file, .m4v format.
- The Blakely Lab - Laboratory exploring the molecular basis for neurotransmitter transporter structure, function and regulation.