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Calcium Is an Inhibitor of Luteinizing Hormone-Sensitive Adenylate Cyclase in the Luteal Cell^*

Reproductive Biology Section, Departments of Obstetrics and Gynecology and Pharmacology, Yale University School of Medicine New Haven, Connecticut 06510

Address requests for reprints to: Dr. Harold R. Behrman, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 3333, New Haven, Connecticut 06510.

Abstract

Both prostaglandin F₂ (PGF₂) and LHRH inhibit LH-stimulated cAMP accumulation and progesterone secretion in the intact luteal cell, but have no effect on LH-sensitive adenylate cyclase activity in isolated membranes. The present studies were conducted to assess the possibility that calcium (Ca²⁺) may mediate the inhibitory activity of PGF₂ and LHRH in the rat luteal cell. Removal of extracellular Ca²⁺ significantly enhanced cAMP accumulation in response to LH by about 2-fold, but blunted LH-stimulated progesterone secretion. Incubation of luteal cells with A23187 caused a highly significant and dose-related decrease in LH-stimulated cAMP accumulation with a concentration for half-maximal inhibition (IC₅₀) of about 1 µ_m. No effect of A23187 was seen on LH-sensitive adenylate cyclase activity, but the ionophore elicited significant inhibition of LH-stimulated intracellular cAMP accumulation in the presence of isobutyl-methylxanthine (MIX), a phosphodiesterase inhibitor. Inhibition by A23187 was Ca²⁺ dependent, since a decrease in extracellular Ca²⁺ to less than 100 µM completely blocked the effect of the ionophore. A23187 also significantly inhibited LH-stimulated progesterone secretion in response to LH or cholera toxin and inhibited cholera toxin-stimulated cAMP accumulation in the absence or presence of MIX. In incubations of isolated luteal membranes, Ca²⁺ produced a dose-dependent inhibition of LH-stimulated adenylate cyclase activity in the absence or presence of MIX at free Ca²⁺ levels between 5–20 nM (IC₅₀), 10 µM). Depletion of extra-cellular Ca²⁺ had no effect on inhibition of LH-stimulated cAMP accumulation by PGF₂ in the intact cell, and the inhibitory activity of LHRH was slightly reduced, but not abolished, by depletion of extracellular Ca²⁺. Verapamil, a Ca²⁺ channel blocker, had no effect on inhibition of LH-stimulated cAMP accumulation by PGF₂ or LHRH.

It is concluded that an acute increase in intracellular Ca²⁺ inhibits activation of adenylate cyclase by LH in the rat luteal cell. This conclusion is based on studies that showed enhanced cAMP accumulation by LH in Ca²⁺-depleted media, Ca²⁺-dependent inhibition of LH-stimulated cAMP production by a Ca²⁺ ionophore, and direct inhibition of LH-sensitive adenylate cyclase activity by Ca²⁺ in luteal membranes. It is suggested that a similar effect occurs in response to PGF₂ or LHRH in the luteal cell, but inhibition by these luteolytic agents is not dependent on an influx of extracellular Ca²⁺, but, rather, is due to an increase in intracellular Ca²⁺ by other mechanisms. (Endocrinology 114: 1208, 1984)

Footnotes

^* This work was supported by NIH Grants HD-15403 and HD-10718.

Received May 18, 1983.

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