SLC22A3 explained

Solute carrier family 22 member 3 (SLC22A3) also known as the organic cation transporter 3 (OCT3) or extraneuronal monoamine transporter (EMT) is a protein that in humans is encoded by the SLC22A3 gene.

Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. This gene is one of three similar cation transporter genes located in a cluster on chromosome 6. The encoded protein contains twelve putative transmembrane domains and is a plasma integral membrane protein.

Distribution

OCT3 is widely distributed in brain tissue. It is not yet completely clear whether its location is primarily neuronal or glial. Areas of the brain in which it has been reported include: hippocampus, retrosplenial cortex, visual cortex, hypothalamus, amygdala, nucleus accumbens, thalamus, raphe nucleus, subiculum, superior and inferior colliculi, and islands of Calleja.

Pharmacology

Organic cation transporter 3 is a polyspecific transporter whose transport is independent of sodium. Known substrates for transport include: histamine, serotonin, norepinephrine, dopamine and MPP⁺. Capacity for transport and affinity for these substrates may vary between rat and human isoforms however.

Transport activity of OCT3 is inhibited by recreational and pharmaceutical drugs, including MDMA, phencyclidine (PCP), MK-801, amphetamine, methamphetamine and cocaine. Transport is also inhibited by the chemical decynium-22 and physiological concentrations of corticosterone and cortisol. K_i values for decynium-22 and corticosterone inhibition of OCT3 transport are respectively 10 and 100 times lower than K_i values of OCT1 and OCT2. This effect of glucocorticoids is believed to explain the phenomenon of stress-induced relapse in recovering addicts, where dopamine transport inhibition causes reactivation of hypersensitive dopamine pathways involved in drug-seeking behavior and incentive salience.

See also

• Solute carrier family

Further reading

• Wu X, Kekuda R, Huang W, etal . Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. . J. Biol. Chem. . 273 . 49 . 32776–32786 . 1999 . 9830022 . 10.1074/jbc.273.49.32776 . free .
• Gründemann D, Schechinger B, Rappold GA, Schömig E . Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. . Nat. Neurosci. . 1 . 5 . 349–351 . 1999 . 10196521 . 10.1038/1557 . 8355270 .
• Gründemann D, Schömig E . Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. . Hum. Genet. . 106 . 6 . 627–635 . 2000 . 10942111 . 10.1007/s004390000309 . 28444495 .
• Wu X, Huang W, Ganapathy ME, etal . Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney. . Am. J. Physiol. Renal Physiol. . 279 . 3 . F449–58 . 2000 . 10966924 . 10.1152/ajprenal.2000.279.3.F449. 12385921 .
• Wieland A, Hayer-Zillgen M, Bönisch H, Brüss M . Analysis of the gene structure of the human (SLC22A3) and murine (Slc22a3) extraneuronal monoamine transporter. . Journal of Neural Transmission . 107 . 10 . 1149–1157 . 2001 . 11129104 . 10.1007/s007020070028 . 9706545 .
• Wessler I, Roth E, Deutsch C, etal . Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters. . Br. J. Pharmacol. . 134 . 5 . 951–956 . 2001 . 11682442 . 10.1038/sj.bjp.0704335 . 1573028 .
• Martel F, Keating E, Calhau C, etal . Regulation of human extraneuronal monoamine transporter (hEMT) expressed in HEK293 cells by intracellular second messenger systems. . Naunyn-Schmiedeberg's Arch. Pharmacol. . 364 . 6 . 487–495 . 2002 . 11770002 . 10.1007/s002100100476 . 21499579 .
• Hayer-Zillgen M, Brüss M, Bönisch H . Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. . Br. J. Pharmacol. . 136 . 6 . 829–836 . 2003 . 12110607 . 10.1038/sj.bjp.0704785 . 1573414 .
• Gründemann D, Hahne C, Berkels R, Schömig E . Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2). . J. Pharmacol. Exp. Ther. . 304 . 2 . 810–817 . 2003 . 12538837 . 10.1124/jpet.102.044404 . 11496882 .
• Lazar A, Gründemann D, Berkels R, etal . Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). . J. Hum. Genet. . 48 . 5 . 226–230 . 2003 . 12768439 . 10.1007/s10038-003-0015-5 . free .
• Haag C, Berkels R, Gründemann D, etal . The localisation of the extraneuronal monoamine transporter (EMT) in rat brain. . J. Neurochem. . 88 . 2 . 291–297 . 2004 . 14690517 . 10.1111/j.1471-4159.2004.02180.x . 45854898 . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nat. Genet. . 36 . 1 . 40–45 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Bottalico B, Larsson I, Brodszki J, etal . Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. . Placenta . 25 . 6 . 518–529 . 2004 . 15135235 . 10.1016/j.placenta.2003.10.017 .
• Jiang W, Prokopenko O, Wong L, etal . IRIP, a new ischemia/reperfusion-inducible protein that participates in the regulation of transporter activity. . Mol. Cell. Biol. . 25 . 15 . 6496–6508 . 2005 . 16024787 . 10.1128/MCB.25.15.6496-6508.2005 . 1190334 .
• Bourdet DL, Pritchard JB, Thakker DR . Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). . J. Pharmacol. Exp. Ther. . 315 . 3 . 1288–1297 . 2006 . 16141367 . 10.1124/jpet.105.091223 . 1633259 .
• Aoyama N, Takahashi N, Kitaichi K, etal . Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder. . Alcohol. Clin. Exp. Res. . 30 . 10 . 1644–1649 . 2006 . 17010131 . 10.1111/j.1530-0277.2006.00215.x .
• Bottalico B, Noskova V, Pilka R, etal . The organic cation transporters (OCT1, OCT2, EMT) and the plasma membrane monoamine transporter (PMAT) show differential distribution and cyclic expression pattern in human endometrium and early pregnancy decidua. . Mol. Reprod. Dev. . 74 . 10 . 1303–1311 . 2007 . 17393420 . 10.1002/mrd.20697 . 25378552 .