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Gonadotropin-Releasing Hormone Stimulates Luteinizing Hormone Secretion By Extracellular Calcium-Dependent and -Independent Mechanisms^*

JOHN P. CHANG, STANKO S. STOJILKOVI, JANELLE S. GRAETER and KEVIN J. CATT

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Kevin J. Catt, Building 10, Room 8C 407, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892.

Abstract

The dependence of LH responses to GnRH on extracellular calcium was investigated in cultured rat pituitary cells exposed to GnRH for 3 h in static culture or for 2 min during column perifusion. During static culture in normal medium, LH release was stimulated by GnRH with an ED₅₀ of 0.3 nM and by K⁺ with an ED₅₀ of 32 mM. Incubation in Ca²⁺- deficient (no added Ca²⁺) or Ca²⁺-free medium (containing 100 µM EGTA) substantially decreased, but did not abolish, the LH responses to 10 and 100 nM GnRH, whereas K⁺-induced LH release was almost completely abolished in Ca²⁺-deficient medium. The Ca²⁺ channel agonist (BK 8644) and antagonists (nifedipine, nicardipine, verapamil, and Co²⁺) respectively enhanced or reduced the LH responses to both GnRH and K⁺. However, the calcium antagonists completely abolished the LH response to depolarization by K⁺, but only partially inhibited the LH response to GnRH, confirming the existence of a significant component of GnRH action that is not dependent on extracellular Ca²⁺. In perifused pituitary cells, exposure to Ca²⁺- deficient medium or normal medium containing 5 mM EGTA or 5 mM EDTA, reduced the initial rapid LH response to 2-min pulses of 10 nM GnRH and abolished the second phase of LH release. Reintroduction of Ca²⁺-containing medium at the end of the GnRH pulse caused recovery of the second phase of LH secretion, demonstrating that influx of extracellular Ca²⁺ is not required for the early phase of the LH response to GnRH but, rather, appears to be essential for its prolongation. The release of LH in response to arachidonic acid, which has been implicated in the mechanism of the secretory action of GnRH, was completely independent of extracellular Ca²⁺ and unaffected by addition of 10 nM BK 8644.

These observations indicate that the initiation of the secretory response to GnRH is largely independent of calcium entry, whereas the prolongation of gonadotropin secretion is maintained by calcium influx, in part through voltage-sensitive calcium channels. The role of arachidonic acid metabolites in GnRH action is probably related to the calcium-independent component of GnRH-induced LH secretion. Since GnRH is secreted episodically and for short periods, much of its physiological action on pulsatile gonadotropin release could be independent of calcium influx from the extracellular fluid. (Endocrinology 122: 87–97,1988)

Footnotes

^* This work was presented in abstract form at the 69th Annual Meeting of the Endocrine Society, Indianapolis, Indiana, 1987 (Abstract 154).

Supported by an Alberta Heritage Foundation for Medical Research Postdoctoral Fellowship.

Recipient of fellowships from the International Atomic Energy Agency and Sigma Tau (Rome, Italy).

Received February 6, 1987.

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