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1 Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, and 2 Klinik und Poliklinik für Kinderheilkunde, Universitätsklinikum Münster, D-48149 Münster; and 3 Institut für Anatomie und Zellbiologie, Universität Würzburg, D-97070 Würzburg, Germany
Properties and regulation of the human organic cation (OC) transporter type 2 (hOCT2) expressed in HEK-293 cells were extensively characterized using the fluorescent OC 4-[4-(dimethylamino)styryl]-N-methylpyridinium (ASP+). ASP+ uptake was electrogenic and inhibited by TPA+ (EC50 = 2.7 µM), tetraethylammonium (EC50 = 35 µM), cimetidine (EC50 = 36 µM), or quinine (EC50 = 6.7 µM). Stimulation with carbachol or ATP decreased initial uptake by 44 ± 3 (n = 14) and 34 ± 4% (n = 21), respectively, independently of PKC but dependent on phosphatidylinositol 3-kinase (PI3K). PKA stimulation decreased uptake by 18 ± 4% (n = 40). Inhibition of calmodulin (CaM), Ca2+/CaM-dependent kinase II, or myosin light chain kinase decreased uptake by 63 ± 2 (n = 15), 40 ± 4 (n = 30), and 31 ± 4% (n = 16), respectively. Inhibition of CaM resulted in a significant change in the EC50 value for the inhibition of ASP+ uptake by tetraethylammonium. In conclusion, we demonstrate that the hOCT2 is inhibited by PI3K and PKA and activated by a CaM-dependent signaling pathway, probably via a change in substrate affinity.
organic cation transport; human organic cation transporter type 2; human; calcium/calmodulin; calcium/calmodulin-dependent kinase II; myosin light chain kinase; phospholipase C; protein kinase C; protein kinase A; phosphatidylinositol 3-kinase; electrophysiology; fluorescence microscopy; 4-[4-(dimethylamino)styryl]-N-methylpyridinium
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