Diacylglycerols and protein kinase C. Potential amplifying mechanism for Ca2+-mediated gonadotropin-releasing hormone-stimulated luteinizing hormone release.
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 luteinizing hormone (LH) release by a mechanism which does not require extracellular calcium. We have examined a diacylglycerol and a phorbol ester, which both activate protein kinase C and stimulate LH release. These compounds show synergistic action with calcium ionophore A23187 as secretogogues. Pimozide (a calmodulin antagonist), methoxyverapamil (a calcium 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 on 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.
Harris
C E
CE
Staley
D
D
Conn
P M
PM
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology*; D005260:Female; D005989:Glycerides / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism; D010906:Pituitary Hormone-Releasing Hormones / Q000494:pharmacology*; D011493:Protein Kinase C; D011494:Protein Kinases / Q000502:physiology*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004075:Diglycerides; D005989:Glycerides; D010906:Pituitary Hormone-Releasing Hormones; D000001:Calcimycin; D007986:Luteinizing Hormone; D011494:Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium