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Mechanisms of Arginine-Vasopressin-Induced Ca²⁺ Oscillations in ß-Cells (HIT-T15): A Role for Oscillating Protein Kinase C

Institut für Pharmakologie (M.S.), Charité-Universitätsmedizin Berlin, 14195 Berlin, Germany; and Abteilung für Nephrologie (H.M.) and Abteilung für Gastroenterologie, Hepatologie, und Endokrinologie (S.S., A.G., R.I., G.R., C.S.), Medizinische Hochschule Hannover, 30623 Hannover, Germany

Address all correspondence and requests for reprints to: Dr. Christof Schöfl, Abteilung für Gastroenterologie, Hepatologie, und Endokrinologie, Medizinische Hochschule Hannover, 30623 Hannover, Germany. E-mail: schoefl.christof{at}mh-hannover.de.

We examined the role of protein kinase C (PKC) for the generation of arginine-vasopressin (AVP)-linked Ca²⁺ oscillations in ß-cells (HIT-T15). Activation of PKC by phorbol-12,13-dibutyrate (PDBu) reduced the frequency and finally abolished AVP-induced Ca²⁺ oscillations. The PKC inhibitors Gö 6976, Ro-32-0432, or chelerythrine converted Ca²⁺ oscillations to a plateau-like rise in cytosolic free Ca²⁺, and PKC down-regulation reduced the percentage of cells exhibiting AVP-induced Ca²⁺ oscillations. Several mechanisms were identified by which PKC could exert feedback on the AVP-linked Ca²⁺ oscillator. PDBu, but not the PKC inhibitors, inhibited AVP-stimulated inositol 1,4,5-trisphosphate production and mobilization of internal Ca²⁺. Ca²⁺ influx through voltage-sensitive Ca²⁺ channels was attenuated by PDBu and PKC inhibitors, indicating complex PKC-dependent regulation of voltage-sensitive Ca²⁺ channels involving stimulatory as well as inhibitory components. Furthermore, AVP caused oscillatory translocation of yellow fluorescent protein (YFP)-tagged PKC and PKCßI to the plasma membrane, which paralleled the Ca²⁺ oscillations in single cells. Repetitive translocation of YFP-PKC and -PKCßI could also be elicited by repetitive release of caged Ca²⁺. By contrast, AVP-stimulated translocation of YFP-PKC was monophasic, not synchronized with Ca²⁺ oscillations, and could not be mimicked by release of caged Ca²⁺. In conclusion, undisturbed activation of PKCs is a necessary intermediate to generate or maintain AVP-induced Ca²⁺ oscillations in pancreatic ß-cells. The data further suggest that classical PKCs, predominantly by inhibition of inositol 1,4,5-trisphosphate production, provide the negative feedback required for AVP-induced Ca²⁺ oscillations to occur that is mediated by their repetitive activation by oscillating Ca²⁺ concentrations.

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