title: The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3.
abstract: The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. Protein kinase signaling mediates rapid modulation of cerebral processes, but little is known about acute regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3) and generated a human embryonic kidney cell line stably expressing the transporter to study transport characteristics, acute regulation by protein kinases, and interaction with psychotropic drugs. Uptake measurement was performed using the fluorescent cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+), 1 μM) as a substrate. The translational value of these findings was determined by comparing results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium, tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine are significantly different. Diazepam is a non-transported inhibitor. Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56 (lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT present, confirmed this regulation pathway. Only the activity of hOCT3 is regulated by calmodulin. These findings suggest that even though many transport properties of mOCT3 and hOCT3 are similar, there are also species-specific aspects of OCT3 function.
authors: Experimental Nephrology, Department of Internal Medicine D, University of Münster, Albert-Schweitzer-Campus 1 (A14), 48149, Münster, Germany.
authors: Vivian
authors: V
authors: Massmann
authors: Bayram
authors: B
authors: Edemir
authors: Eberhard
authors: E
authors: Schlatter
authors: Rouvier
authors: R
authors: Al-Monajjed
authors: Saliha
authors: S
authors: Harrach
authors: Philipp
authors: P
authors: Klassen
authors: Svenja K
authors: SK
authors: Holle
authors: Aleksandra
authors: A
authors: Sindic
authors: Marina
authors: M
authors: Dobrivojevic
authors: Hermann
authors: H
authors: Pavenstädt
authors: Giuliano
authors: G
authors: Ciarimboli
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003975:Diazepam / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology*; D057809:HEK293 Cells; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*; D013045:Species Specificity; D000099254:Organic Cation Transporter 3
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D003975:Diazepam; D005473:Fluoxetine; D006632:Histamine; D007649:Ketamine; D050814:Octamer Transcription Factor-3; D027701:Organic Cation Transport Proteins; D011619:Psychotropic Drugs; D000644:Quaternary Ammonium Compounds; D012701:Serotonin; D000099254:Organic Cation Transporter 3; C494174:Pou5f1 protein, mouse; C027435:tetrapentylammonium
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