The relationship between gonadotropin-releasing hormone-stimulated luteinizing hormone release and inositol phosphate production: studies with calcium antagonists and protein kinase C activators.
The coupling between GnRH-stimulated phosphoinositide (PI) turnover and LH release has been investigated in rat pituitary cell cultures. Accumulation of [3H]inositol phosphates ([3H]IPs) formed by hydrolysis of PIs was measured in cells that had been preloaded with [3H]myo-inositol. GnRH stimulated both LH release and incorporation of [3H]inositol into total [3H]IPs with similar dose and time dependencies. [3H] IP production in response to GnRH could be blocked by a GnRH antagonist, but was stimulated by a compound that provokes receptor microaggregation. GnRH-stimulated IP production persisted in the presence of either the Ca2+ channel blocker D600 or the calmodulin antagonist pimozide at concentrations that reduced LH release to 60% and 20% of control, respectively. Stimulated [3H]IP production was inhibited at higher concentrations of D600. In 1-h incubations, GnRH-stimulated [3H]IP production, but not LH release, was markedly inhibited by the protein kinase C activators phorbol myristate acetate and 1,2-dioctanoylglycerol. These findings indicate that in the gonadotrope, GnRH-stimulated LH release and [3H]IP production are closely coupled to receptor activation by an agonist; Ca2+ antagonists uncouple stimulated LH release from [3H]IP production; and protein kinase C activators uncouple stimulated PI turnover from LH release. Thus, GnRH-stimulated production of PI metabolites, as measured by [3H]IP accumulation, is apparently not sufficient to support LH release in the absence of Ca2+. In addition, GnRH-stimulated LH release is apparently not dependent on full expression of the PI response.
D000818:Animals; D002118:Calcium / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D004075:Diglycerides / Q000494:pharmacology; D005260:Female; D005711:Gallopamil / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000502:physiology*; D007986:Luteinizing Hormone / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D010868:Pimozide / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000378:metabolism* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011966:Receptors, LHRH / Q000502:physiology; D013403:Sugar Phosphates / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002147:Calmodulin; D004075:Diglycerides; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011966:Receptors, LHRH; D013403:Sugar Phosphates; D010868:Pimozide; D007987:Gonadotropin-Releasing Hormone; D005711:Gallopamil; D007986:Luteinizing Hormone; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium