DIACYLGLYCEROLS AND PROTEIN KINASE-C - POTENTIAL AMPLIFYING MECHANISM FOR CA-2+-MEDIATED GONADOTROPIN-RELEASING HORMONE-STIMULATED LUTEINIZING-HORMONE RELEASE

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Abstract
The present study was designed to test the hypothesis that there is a functional interaction between the calcium-calmodulin system, which appears to mediate the action of gonadotropin-releasing hormone (GnRH), and activators of protein kinase C, which stimulate luteinzing hormone (LH) release by a mechanism which does not require extracellular Ca. A diacylglycerol and a phorbol ester, which both activate protein kinase C and stimulate LH release were examined. These compounds show synergistic action with calcium ionophore A23187 (calcimycin) as secretogogues. Pimozide (a calmodulin antagonist), methoxyverapamil (a Ca ion channel inhibitor), and Ac[D-pCl-Phe1,2-D-Trp3-D-Lys6-D-Ala10]GnRH (a potent gonadotropin-releasing hormone antagonist) were used to show that the diacylglycerol and phorbol ester can stimulate LH release in a manner that is independent of both Ca2+ and calmodulin and do not work by means of a direct action of the GnRH receptor. These observations, coupled with previously published reports that extracellular Ca2+ mobilization is both necessary and sufficient for initiation and perpetuation of GnRH-stimulated LH release, indicate that activation of protein kinase C by endogenous diacylglycerols may serve as an amplifier of the GnRH-stimulated signal which appears to be mediated independently by the Ca2+-calmodulin system.