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{{Short description|Class of membrane transport proteins}}
{{Expand|article|date=November 2007}}
'''[[Neurotransmitter]] transporters''' are a class of [[membrane transport protein]]s that span [[cellular membrane]]s and that serve to carry [[neurotransmitters]] across these membranes and to transport them to specific locations. There are more than twenty types of neurotransmitter transporters.<ref name=Iversen>{{cite journal |author=Iversen L |title=Neurotransmitter transporters: fruitful targets for CNS drug discovery |journal=Mol. Psychiatry |volume=5 |issue=4 |pages=357–62 |year=2000 |month=July |pmid=10889545 |url=http://www.biopsychiatry.com/transporters.htm}}</ref> The transporters exist in the membranes of [[neuron]]s and [[glia]].
'''Neurotransmitter transporters''' are a class of [[membrane transport protein]]s that span the [[cellular membrane]]s 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.<ref name=Iversen>{{cite journal |author=Iversen L |title=Neurotransmitter transporters: fruitful targets for CNS drug discovery |journal=Mol. Psychiatry |volume=5 |issue=4 |pages=357–62 |date=July 2000 |pmid=10889545 |url=http://www.biopsychiatry.com/transporters.htm |doi=10.1038/sj.mp.4000728|doi-access= }}</ref>


'''Vesicular transporters''' move neurotransmitters into [[synaptic vesicle]]s, regulating the concentrations of substances within them.<ref name=Johnson>{{cite journal |author=Johnson J, Tian N, Caywood MS, Reimer RJ, Edwards RH, Copenhagen DR |title=Vesicular neurotransmitter transporter expression in developing postnatal rodent retina: GABA and glycine precede glutamate |journal=J. Neurosci. |volume=23 |issue=2 |pages=518–29 |year=2003 |month=January |pmid=12533612 |url=http://www.jneurosci.org/cgi/content/full/23/2/518}}</ref> 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 vesicle]]s and creating a proton gradient. Then the efflux of protons from the vesicle provides the energy to bring the neurotransmitter into the vesicle.<ref name=Kandel>{{cite book |author=[[Eric R. Kandel|Kandel ER]], Schwartz JH, Jessell TM |title=[[Principles of neural science]] |publisher=McGraw-Hill |location=New York |year=2000 |page=287 |isbn=0-8385-7701-6 |edition=4th}}</ref>
'''Vesicular transporters''' move neurotransmitters into [[synaptic vesicle]]s, regulating the concentrations of substances within them.<ref name=Johnson>{{cite journal |vauthors=Johnson J, Tian N, Caywood MS, Reimer RJ, Edwards RH, Copenhagen DR |title=Vesicular neurotransmitter transporter expression in developing postnatal rodent retina: GABA and glycine precede glutamate |journal=J. Neurosci. |volume=23 |issue=2 |pages=518–29 |date=January 2003 |pmid=12533612 |doi=10.1523/JNEUROSCI.23-02-00518.2003 |doi-access=free |pmc=6741860 }}</ref> Vesicular transporters rely on a [[proton gradient]] created by the [[hydrolysis]] of [[adenosine triphosphate]] (ATP) in order to carry out their work: [[v-ATPase]] hydrolyzes ATP, causing protons to be pumped into the [[synaptic vesicle]]s and creating a proton gradient. Then the efflux of protons from the vesicle provides the energy to bring the neurotransmitter into the vesicle.<ref name=Kandel>{{cite book |author=[[Eric R. Kandel|Kandel ER]], Schwartz JH, Jessell TM |title=Principles of neural science |publisher=McGraw-Hill |location=New York |year=2000 |page=[https://archive.org/details/isbn_9780838577011/page/287 287] |isbn=0-8385-7701-6 |edition=4th|title-link=Principles of neural science }}</ref>


Neurotransmitter transporters frequently use [[electrochemical gradient]]s that exist across cell membranes to carry out their work. For example, some transporters use energy obtained by the [[cotransport]] of [[sodium|Na<sup>+</sup>]] in order to move [[glutamate]] across membranes.
Neurotransmitter transporters frequently use [[electrochemical gradient]]s that exist across cell membranes to carry out their work. For example, some transporters use energy obtained by the [[cotransport]], or [[symport]], of [[sodium|Na<sup>+</sup>]] in order to move [[glutamate]] across membranes. Such neurotransporter cotransport systems are highly diverse, as recent development indicates that uptake systems are generally selective and associate with a specific neurotransmitter.<ref name=Susan>{{cite journal |last1=Amara |first1=Susan G. |last2=Kuhar |first2=Michael J. |year=1993 |title=Neurotransmitter Transporters:Recent Progress |journal=Annual Review of Neuroscience |volume=16 |issue=1 |pages=73–93 |doi=10.1146/annurev.ne.16.030193.000445|pmid=8096377 |url=https://zenodo.org/record/1235039 }}</ref>


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 [[receptor (biochemistry)|receptor]]s and exert their effect. This "nonvesicular release" of neurotransmitters is used by some cells, such as [[amacrine cell]]s in the [[retina]], as a normal form of neurotransmitter release.<ref name=Kandel295>{{cite book |author=[[Eric R. Kandel|Kandel ER]], Schwartz JH, Jessell TM |title=[[Principles of neural science]] |publisher=McGraw-Hill |location=New York |year=2000 |page=295 |isbn=0-8385-7701-6 |edition=4th}}</ref>
Normally, transporters in the [[Synapse|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 [[receptor (biochemistry)|receptor]]s and exert their effect. This "nonvesicular release" of neurotransmitters is used by some cells, such as [[amacrine cell]]s in the [[retina]], as a normal form of neurotransmitter release.<ref name=Kandel295>{{cite book |author=[[Eric R. Kandel|Kandel ER]], Schwartz JH, Jessell TM |title=Principles of neural science |publisher=McGraw-Hill |location=New York |year=2000 |page=[https://archive.org/details/isbn_9780838577011/page/295 295] |isbn=0-8385-7701-6 |edition=4th|title-link=Principles of neural science }}</ref>


== Types ==
== Types ==
{{Synapse map}}

Specific types of neurotransmitter transporters include the following:
Specific types of neurotransmitter transporters include the following:


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** [[Vesicular glutamate transporter 2]] (VGLUT2)
** [[Vesicular glutamate transporter 2]] (VGLUT2)
** [[Vesicular glutamate transporter 3]] (VGLUT3)
** [[Vesicular glutamate transporter 3]] (VGLUT3)

* [[GABA transporter]]s, including:
* [[GABA transporter]]s, including:
** [[GABA transporter type 1]] (GAT1)
** [[GABA transporter type 1]] (GAT1)
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** [[Betaine transporter]] (BGT1)
** [[Betaine transporter]] (BGT1)
** [[Vesicular GABA transporter]] (VGAT)
** [[Vesicular GABA transporter]] (VGAT)

* [[Glycine transporter]]s, including:
* [[Glycine transporter]]s, including:
** [[Glycine transporter type 1]] (GlyT1)
** [[Glycine transporter 1|Glycine transporter type 1]] (GlyT1)
** [[Glycine transporter type 2]] (GlyT2)
** [[Glycine transporter type 2]] (GlyT2)
⚫
* [[Monoamine transporter]]s, including:

⚫
* [[Monoamine transporter]]s including:
** [[Dopamine transporter]] (DAT)
** [[Dopamine transporter]] (DAT)
** [[Norepinephrine transporter]] (NET)
** [[Norepinephrine transporter]] (NET)
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** [[Vesicular monoamine transporter 1]] (VMAT1)
** [[Vesicular monoamine transporter 1]] (VMAT1)
** [[Vesicular monoamine transporter 2]] (VMAT2)
** [[Vesicular monoamine transporter 2]] (VMAT2)

* [[Equilibrative nucleoside transporter|Adenosine transporter]]s, including:
* [[Equilibrative nucleoside transporter|Adenosine transporter]]s, including:
** [[Equilibrative nucleoside transporter 1]] (ENT1)
** [[Equilibrative nucleoside transporter 1]] (ENT1)
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** [[Equilibrative nucleoside transporter 3]] (ENT3)
** [[Equilibrative nucleoside transporter 3]] (ENT3)
** [[Equilibrative nucleoside transporter 4]] (ENT4)
** [[Equilibrative nucleoside transporter 4]] (ENT4)
⚫
* [[Vesicular acetylcholine transporter]] (VAChT)<ref>{{cite journal |vauthors=Weihe E, Tao-Cheng JH, Schäfer MK, Erickson JD, Eiden LE |title=Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles |journal=Proc Natl Acad Sci USA |volume=93 |issue=8 |pages=3547–52 |date=April 1996 |pmid=8622973 |pmc=39647 |doi= 10.1073/pnas.93.8.3547|bibcode=1996PNAS...93.3547W |doi-access=free }}</ref>


⚫
Note that there is no plasmalemmal [[acetylcholine]] transporter, as acetylcholine is terminated via rapid metabolism into [[choline]] by [[cholinesterase]] [[enzyme]]s, and choline is subsequently transported back into the cell and reconverted into acetylcholine.
⚫
* [[Vesicular acetylcholine transporter]] (VAChT)<ref>{{cite journal |author=Weihe E, Tao-Cheng JH, Schäfer MK, Erickson JD, Eiden LE |title=Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles |journal=Proc Natl Acad Sci USA. |volume=93 |issue=8 |pages=3547–52 |year=1996 |month=April |pmid=8622973 |pmc=39647 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8622973}}</ref>

⚫
Note that there is no plasmalemmal [[acetylcholine]] transporter, as acetylcholine is terminated via rapid metabolism into [[choline]] by [[cholinesterase]] [[enzyme]]s, and choline is subsequently transported back into the cell and converted back into acetylcholine.


Transporters associated with [[histamine]] and the [[endocannabinoid]]s have not yet been identified.
Transporters associated with [[histamine]] and the [[endocannabinoid]]s have not yet been identified.
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== Clinical significance ==
== Clinical significance ==


A variety of neurotransmitter reuptake transporters are pharmacotherapeutic targets for modulating the synaptic neurotransmitter concentration, and therefore neurotransmission.
[[Antidepressant]]s act by inhibiting [[norepinephrine]] and [[serotonin]] [[reuptake]] transporters.<ref name=Iversen/>
* [[Antidepressant]]s such as [[selective serotonin reuptake inhibitor|SSRIs]], [[serotonin-norepinephrine reuptake inhibitor|SNRIs]] and [[tricyclic antidepressant|TCAs]] suppress the activity of serotonin and/or norepinephrine transporters, preventing the reuptake of targeted neurotransmitters from the [[synaptic cleft]].
* [[Psychostimulant]]s like [[cocaine]], [[amphetamine]]s, and [[methylphenidate]] act by inhibiting and/or reversing the dopamine and/or norepinephrine transporters. Some [[dissociative]]s like [[phencyclidine]] and [[ketamine]] are also dopamine transporter inhibitors.
* [[Tiagabine]], a drug used as an [[anticonvulsant]], acts by inhibiting the GABA transporter 1.


[[File:Neurotransmitter transporters inhibitors.png|thumb|250px|Neurotransmitter transporters inhibitors]]
[[Cocaine]] and [[phencyclidine]] partially exert their effects by acting on the dopamine transporter.<ref name=Iversen/>


Vesicular transporters could provide an alternative therapeutic target for the modulation of chemical neurotransmission, as the activity of these transporters could affect the quantity of neurotransmitter released.<ref>{{cite journal |vauthors=Varoqui H, Erickson JD |title=Vesicular neurotransmitter transporters. Potential sites for the regulation of synaptic function |journal=Molecular Neurobiology |volume=15 |issue=2 |pages=165–91 | date=October 1997 |pmid=9396009 |doi=10.1007/BF02740633|s2cid=26111849 }}</ref>
The [[anticonvulsant]] drug [[tiagabine]] prevents the reuptake of [[GABA]] by acting on the GABA transporter GAT-1.<ref name=Iversen/>
* [[Vesamicol]], for example, is an inhibitor of the [[vesicular acetylcholine transporter]]. It prevents the loading of ACh into the presynaptic vesicles, causing a fall in the amount that is released in response to a neuronal [[action potential]]. It is ''not'' used clinically, but provides a useful tool for research into the [[Synaptic vesicle#The synaptic vesicle cycle|behaviour]] of neurotransmitter vesicles.<ref>{{cite journal |vauthors=Prior C, Marshall IG, Parsons SM |title=The pharmacology of vesamicol: an inhibitor of the vesicular acetylcholine transporter |journal=General Pharmacology |volume=23 |issue=6 |pages=1017–22 | date=November 1992 |pmid=1487110 |doi=10.1016/0306-3623(92)90280-w}}</ref>


The expression of GABA transporter GAT-1 is decreased in the axonal cartridges of [[chandelier cell]]s in [[schizophrenia]].<ref name=Volk_2001>{{cite journal |author=Volk D, Austin M, Pierri J, Sampson A, Lewis D |title=GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons |journal=Am J Psychiatry |volume=158 |issue=2 |pages=256–65 |year=2001 |month=February |pmid=11156808 |url=http://ajp.psychiatryonline.org/cgi/content/full/158/2/256}}</ref>
== References ==
== References ==
{{Reflist|2}}
{{reflist|30em}}

⚫
== External links ==
⚫
* {{MeshName|Neurotransmitter+Transporters}}
⚫
* [http://videocast.nih.gov/PastEventDetail.asp?13354 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 [[National Institutes of Health|NIH]] Neuroscience Seminar series. 450 Mb file, [[MPEG-4 Part 14|.m4v]] format.
⚫
* [http://web.mac.com/rdblakely/iWeb/BlakelyLab/Home.html The Blakely Lab] - Laboratory exploring the molecular basis for neurotransmitter transporter structure, function and regulation.


⚫
==External links==
{{Commonscat|Neurotransmitter transporters}}
⚫
*{{MeshName|Neurotransmitter+Transporters}}
⚫
*[https://web.archive.org/web/20060929042009/http://videocast.nih.gov/PastEventDetail.asp?13354 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 [[National Institutes of Health|NIH]] Neuroscience Seminar series. 450 Mb file, [[MPEG-4 Part 14|.m4v]] format.
⚫
*[https://web.archive.org/web/20070306012319/http://web.mac.com/rdblakely/iWeb/BlakelyLab/Home.html The Blakely Lab] - Laboratory exploring the molecular basis for neurotransmitter transporter structure, function and regulation.


{{Neurotransmitters}}
{{Neurotransmitters}}
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{{Neurotransmitter transporters}}
{{Neurotransmitter transporters}}


[[Category:Neurotransmitter transporters|*]]
{{DEFAULTSORT:Neurotransmitter Transporter}}
[[Category:Neurotransmitter transporters| ]]
[[Category:Integral membrane proteins]]
[[Category:Integral membrane proteins]]

Latest revision as of 00:34, 19 August 2023

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: v-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, or symport, of Na+ in order to move glutamate across membranes. Such neurotransporter cotransport systems are highly diverse, as recent development indicates that uptake systems are generally selective and associate with a specific neurotransmitter.[4]

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.[5]

Types

[edit]
Structure of a typical chemical synapse

Specific types of neurotransmitter transporters include the following:

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

[edit]

A variety of neurotransmitter reuptake transporters are pharmacotherapeutic targets for modulating the synaptic neurotransmitter concentration, and therefore neurotransmission.

Neurotransmitter transporters inhibitors

Vesicular transporters could provide an alternative therapeutic target for the modulation of chemical neurotransmission, as the activity of these transporters could affect the quantity of neurotransmitter released.[7]

References

[edit]
  1. ^ Iversen L (July 2000). "Neurotransmitter transporters: fruitful targets for CNS drug discovery". Mol. Psychiatry. 5 (4): 357–62. doi:10.1038/sj.mp.4000728. PMID 10889545.
  2. ^ Johnson J, Tian N, Caywood MS, Reimer RJ, Edwards RH, Copenhagen DR (January 2003). "Vesicular neurotransmitter transporter expression in developing postnatal rodent retina: GABA and glycine precede glutamate". J. Neurosci. 23 (2): 518–29. doi:10.1523/JNEUROSCI.23-02-00518.2003. PMC 6741860. PMID 12533612.
  3. ^ 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)
  4. ^ Amara, Susan G.; Kuhar, Michael J. (1993). "Neurotransmitter Transporters:Recent Progress". Annual Review of Neuroscience. 16 (1): 73–93. doi:10.1146/annurev.ne.16.030193.000445. PMID 8096377.
  5. ^ 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)
  6. ^ Weihe E, Tao-Cheng JH, Schäfer MK, Erickson JD, Eiden LE (April 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. Bibcode:1996PNAS...93.3547W. doi:10.1073/pnas.93.8.3547. PMC 39647. PMID 8622973.
  7. ^ Varoqui H, Erickson JD (October 1997). "Vesicular neurotransmitter transporters. Potential sites for the regulation of synaptic function". Molecular Neurobiology. 15 (2): 165–91. doi:10.1007/BF02740633. PMID 9396009. S2CID 26111849.
  8. ^ Prior C, Marshall IG, Parsons SM (November 1992). "The pharmacology of vesamicol: an inhibitor of the vesicular acetylcholine transporter". General Pharmacology. 23 (6): 1017–22. doi:10.1016/0306-3623(92)90280-w. PMID 1487110.
[edit]
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