Protein kinase C potentiation of the tyrosine kinase inhibitor-stimulated cyclic GMP production in rat pinealocytes.
Inhibition of tyrosine kinase activities elevates cyclic GMP (cGMP) levels in rat pinealocytes. Since protein kinase C (PKC) and intracellular Ca2+ both interact with the agonist-stimulated cGMP accumulation, in this study their interactions with the tyrosine kinase inhibitor-mediated cGMP response were investigated. Two tyrosine kinase inhibitors, genistein and tyrphostin B42, increased basal cGMP accumulation concentration dose-dependently. This increase in cGMP accumulation was potentiated by 4 beta-phorbol 12-myristate 13-acetate (PMA), an activator of PKC, and blocked by calphostin C, a specific PKC inhibitor. The tyrosine kinase inhibitors had no effect on the in vitro or PMA-mediated translocation of PKC activity. However, when the phosphodiesterase was inhibited by isobutylmethylxanthine (IBMX), neither the tyrosine kinase inhibitors alone nor in combination with PMA had an effect on cGMP accumulation, suggesting that phosphodiesterase is a probable site of action of the inhibitors. In comparison, elevation of intracellular Ca2+ by BayK 8644, ionomycin, or KCl inhibited the genistein- or tyrphostin B42-mediated increase in cGMP accumulation. This inhibition persisted in the presence of IBMX and was partly reversed by a Ca2+/calmodulin inhibitor. These results suggest that PKC modulates the rate of cGMP degradation through signalling pathways involving tyrosine phosphorylation. However, the inhibitory effect of the Ca(2+)-elevating agents on the tyrosine kinase inhibitor-stimulated cGMP accumulation appears to be independent of phosphodiesterase inhibition.
Ogiwara
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Department of Physiology, Faculty of Medicine, University of Alberta, Edmonton, Canada.
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis*; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D010870:Pineal Gland / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007529:Isoflavones; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D006152:Cyclic GMP; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium