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Articles in PresS, published online ahead of print October 15, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00251.2002
Submitted on July 11, 2002
Accepted on October 9, 2002
1 Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitatsklinikum Munster, Munster, Germany; Klinik und Poliklinik fur Kinderheilkunde, Universitatsklinikum Munster, Munster, Germany
2 Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitatsklinikum Munster, Munster, Germany
3 Institut fur Anatomie und Zellbiologie, Universitat Wurzburg, Wurzburg, Germany
* To whom correspondence should be addressed. E-mail: eberhard.schlatter{at}uni-muenster.de.
Properties and regulation of the human organic cation (OC) transporter type 2 (hOCT2) expressed in HEK293 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), TEA+ (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, independent on protein kinase C (PKC), but dependent on phosphatidylinositol 3-kinase (PI3K). Protein kinase A (PKA) stimulation decreased uptake by 18±4% (n=40). Inhibition of calmodulin (CaM), the Ca2+/CaM dependent kinase II, or the 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 TEA+. In conclusion we demonstrate that the hOCT2 is inhibited by PI3K and PKA and activated by CaM dependent signaling pathway probably via a change in substrate affinity.
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