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J Am Soc Nephrol 11:1216-1224, 2000
© 2000 American Society of Nephrology

REGULAR ARTICLES

The Affinity of the Organic Cation Transporter rOCT1 Is Increased by Protein Kinase C-Dependent Phosphorylation

THOMAS MEHRENS*, SILKE LELLECK*, IBRAHIM ÇETINKAYA*, MARION KNOLLMANN*, HELGE HOHAGE*, VALENTIN GORBOULEV{ddagger}, PETER BOKNÍK{dagger}, HERMANN KOEPSELL{ddagger} and EBERHARD SCHLATTER*

* Medizinische Poliklinik, Experimentelle Nephrologie, Westfälische Wilhelms-Universität Münster, Germany
{dagger} Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität Münster, Germany
{ddagger} Anatomisches Institut, Universität Würzburg, Germany.

Correspondence to Dr. Eberhard Schlatter, Medizinische Poliklinik, Experimentelle Nephrologie, Westfälische Wilhelms-Universität Münster, Domagkstraße 3a, D-48149 Münster, Germany. Phone : +49 2518 356991 ; Fax : +49 2518 356973 ; E-mail : schlate{at}uni-muenster.de

Abstract. Members of the organic cation transporter (OCT) family are mainly expressed in kidney, liver, intestine, and brain. The regulation of the OCT type 1 from rat (rOCT1) stably transfected in HEK293 cells was examined using a fluorimetric technique, 1-[3H]methyl-4-phenylpyridinium uptake studies, and fast-whole-cell patch-clamp recordings. For the fluorescence measurements, the cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP+) was used as substrate. Uptake of ASP+ via rOCT1 was electrogenic, and its inhibition by other organic cations was consistent with previously reported radioactive tracer flux measurements. The inhibitor quinine was not translocated by the organic cation transporter in contrast to tetraethylammonium. Stimulation of diacyl glycerol-dependent protein kinase C (PKC) by sn-1,2-dioctanoyl glycerol (1 µM) resulted in an increase in initial ASP+ uptake rate by 216 ± 28% (n = 29). The effect was completely antagonized by the PKC inhibitor tamoxifen (20 µM, n = 22). Forskolin (1 µM), which activates adenylate cyclase and thereby protein kinase A (PKA), stimulated the initial rate of ASP+ accumulation by 51 ± 6% (n = 19). This effect was inhibited by the specific PKA inhibitor KT5720 (1 µM, n = 12). Inhibition of tyrosine kinases by aminogenestein (10 µM) reduced ASP+ uptake by 63 ± 7% (n = 7), while genestein or tyrphostin AG1295 (each 10 µM) were without significant effects. Incubation of the cells with sn-1,2-dioctanoyl glycerol (1 µM) increased the affinities of the transporter to tetraethylammonium, tetrapenthylammonium, and quinine by a factor of 58, 14.5, and 2.4, respectively. Western blot analysis revealed that rOCT1 protein was phosphorylated at a serine residue upon stimulation of PKC. In conclusion, it has been demonstrated that the organic cation transport by rOCT1 is stimulated by PKC, PKA, and endogenous tyrosine kinase activation. The PKC phosphorylates rOCT1 and leads to a conformational change at the substrate binding site.




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