Reverse transport

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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.[1][2][3][4][5] 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.[1][2]

The primary function of most neurotransmitter transporters is to facilitate neurotransmitter reuptake (i.e., the reabsorption of neurotransmitters by the cell which released them).[1][2][6] During neurotransmitter reuptake, neurotransmitter transporters will move specific types of neurotransmitters from the extracellular space into the cytosol of a neuron or glial cell.[1][2][6] 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).[1][2] 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, many monoamine releasing agents 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).[1][2][7]

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  1. ^ a b c d e f Bermingham DP, Blakely RD (October 2016). "Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters". Pharmacol. Rev. 68 (4): 888–953. doi:10.1124/pr.115.012260. PMC 5050440. PMID 27591044.
  2. ^ a b c d e f Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
  3. ^ Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH (2002). "The role of zinc ions in reverse transport mediated by monoamine transporters". The Journal of Biological Chemistry. 277 (24): 21505–13. doi:10.1074/jbc.M112265200. PMID 11940571.
  4. ^ Robertson SD, Matthies HJ, Galli A (2009). "A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters". Molecular Neurobiology. 39 (2): 73–80. doi:10.1007/s12035-009-8053-4. PMC 2729543. PMID 19199083.
  5. ^ Kasatkina LA, Borisova TA (November 2013). "Glutamate release from platelets: exocytosis versus glutamate transporter reversal". The International Journal of Biochemistry & Cell Biology. 45 (11): 2585–2595. doi:10.1016/j.biocel.2013.08.004. PMID 23994539.
  6. ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 3: Synaptic Transmission". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 61–65. ISBN 9780071481274.
  7. ^ Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216 (1): 86–98. Bibcode:2011NYASA1216...86E. doi:10.1111/j.1749-6632.2010.05906.x. PMC 4183197. PMID 21272013. 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.