reverse transport
Reverse transport, or transporter reversal, is a phenomenon in which the substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter.{{cite journal | vauthors = Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH | title = The role of zinc ions in reverse transport mediated by monoamine transporters | journal = The Journal of Biological Chemistry | volume = 277 | issue = 24 | pages = 21505–13 | year = 2002 | pmid = 11940571 | doi = 10.1074/jbc.M112265200 | doi-access = free }}{{cite journal | vauthors = Robertson SD, Matthies HJ, Galli A | title = A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters | journal = Molecular Neurobiology | volume = 39 | issue = 2 | pages = 73–80 | year = 2009 | pmid = 19199083 | pmc = 2729543 | doi = 10.1007/s12035-009-8053-4 }}{{cite journal | vauthors = Kasatkina LA, Borisova TA | title = Glutamate release from platelets: exocytosis versus glutamate transporter reversal | journal = The International Journal of Biochemistry & Cell Biology | volume = 45 | issue = 11 | pages = 2585–2595 | date = November 2013 | pmid = 23994539 | doi = 10.1016/j.biocel.2013.08.004 }} Transporter reversal typically occurs when a membrane transport protein is phosphorylated by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins.{{cite journal | vauthors = Bermingham DP, Blakely RD | title = Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters | journal = Pharmacol. Rev. | volume = 68 | issue = 4 | pages = 888–953 | date = October 2016 | pmid = 27591044 | doi = 10.1124/pr.115.012260 | pmc=5050440}}{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–176 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}
The primary function of most neurotransmitter transporters is to facilitate neurotransmitter reuptake (i.e., the reabsorption of neurotransmitters by the cell which released them). During neurotransmitter reuptake, neurotransmitter transporters will move specific types of neurotransmitters from the extracellular space into the cytosol of a neuron or glial cell.{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 61–65 | edition = 2nd | chapter = Chapter 3: Synaptic Transmission }} When these transporters operate in reverse, they produce neurotransmitter efflux (i.e., the movement of neurotransmitters from the cytosol to the extracellular space via transporter-mediated release, as opposed to exocytotic release). In neurons, transporter reversal facilitates the release of neurotransmitters into the synaptic cleft, resulting in a higher concentration of synaptic neurotransmitters and increased signaling through the corresponding neurotransmitter receptors.
For example, monoamine releasing agents, such as amphetamines, cause monoamine neurotransmitter efflux (i.e., the release of monoamine neurotransmitters from neurons into the synaptic cleft via monoamine transporter-mediated release) by triggering reverse transport at vesicular monoamine transporters (specifically, VMAT1 and VMAT2) and other monoamine transporters that are located along the plasma membrane of neurons (specifically, DAT, NET, and SERT).{{cite journal |vauthors=Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Ann. N. Y. Acad. Sci. | volume = 1216 | pages = 86–98 | date=January 2011 | issue = 1 | pmid = 21272013 | pmc=4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | bibcode = 2011NYASA1216...86E | quote = VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.}} The exact mechanisms by which amphetamines and other monoamine releasing agents mediate induction of reverse transport are poorly understood.{{cite journal | vauthors = Sulzer D, Sonders MS, Poulsen NW, Galli A | title = Mechanisms of neurotransmitter release by amphetamines: a review | journal = Prog Neurobiol | volume = 75 | issue = 6 | pages = 406–433 | date = April 2005 | pmid = 15955613 | doi = 10.1016/j.pneurobio.2005.04.003 | url = }}{{cite journal | vauthors = Reith ME, Gnegy ME | title = Molecular Mechanisms of Amphetamines | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 258 | issue = | pages = 265–297 | date = 2020 | pmid = 31286212 | doi = 10.1007/164_2019_251 | isbn = 978-3-030-33678-3 | url = }}{{cite book | vauthors = Vaughan RA, Henry LK, Foster JD, Brown CR | title = Pharmacological Advances in Central Nervous System Stimulants | chapter = Post-translational mechanisms in psychostimulant-induced neurotransmitter efflux | series = Adv Pharmacol | volume = 99 | pages = 1–33 | date = 2024 | pmid = 38467478 | doi = 10.1016/bs.apha.2023.10.003 | isbn = 978-0-443-21933-7 | chapter-url = https://books.google.com/books?id=2Sr6EAAAQBAJ&pg=PA1 }} However, the process may involve intracellular calcium ion (Ca2+) elevation, protein kinase C (PKC) activation, and Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) activation.