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Volume 271, Number 39, Issue of September 27, 1996 pp. 23711-23717
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Desensitization of Gonadotropin-releasing Hormone Action in T3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca²⁺ Mobilization

(Received for publication, May 21, 1996, and in revised form, July 1, 1996)

Craig A. McArdle , Gary B. Willars ^¶ , Robert C. Fowkes , Stefan R. Nahorski ^¶ , James S. Davidson and Wyn Forrest-Owen

From the  Department of Medicine, Bristol University, Bristol, BS2 8HW, United Kingdom, the ^¶ Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom, and the  Department of Chemical Pathology, University of Cape Town, Observatory 7925, South Africa

Gonadotropin-releasing hormone (GnRH) acts via a G-protein coupled receptor on gonadotropes to increase cytosolic Ca²⁺ and stimulate gonadotropin secretion. Sustained exposure causes desensitization of these effects, but the GnRH receptor has no C-terminal tail and does not undergo rapid (<5 min) desensitization. Nevertheless, pretreatment of T3-1 cells with GnRH reduced the spike Ca²⁺ response to GnRH and decreased the GnRH effect on inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) by 30-50%. Ca²⁺-free medium with or without thapsigargin also decreased GnRH-stimulated Ins(1,4,5)P₃ generation, implying that attenuation of the Ca²⁺ response underlies the Ins(1,4,5)P₃ reduction rather than vice versa. Intracellular Ca²⁺ pool depletion cannot explain desensitization of the Ca²⁺ response because pool depletion and repletion were faster (half-times, <1 min) than the onset of and recovery from desensitization (half-times 10-20 min and 4-6 h). Moreover, 1-h GnRH pre-treatment attenuated the spike Ca²⁺ response to GnRH but not that to ionomycin, and brief GnRH exposure in Ca²⁺-free medium reduced the response to ionomycin more effectively in controls than in desensitized cells. GnRH pretreatment also attenuated the Ca²⁺ response to PACAP38. This novel form of desensitization does not reflect uncoupling of GnRH receptors from their immediate effector system but rather a reduced efficiency of mobilization by Ins(1,4,5)P₃ of Ca²⁺ from an intact intracellular pool.

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