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Microaggregation of the Gonadotropin-Releasing Hormone-Receptor: Relation to Gonadotrope Desensitization^*

Department of Pharmacology, Duke University Medical Center Durham, North Carlina 27710

Address correspondence and requests for reprints to: P. Michael Conn, Department of Pharmacology, Box 3813, Duke University Medical Center, Durham, North Carolina 27710.

Abstract

Desensitization of the pituitary gonadotrope was examined using perifusion of immobilized dispersed cells. Specifically, a relatively brief (20 min) pulse of GnRH was shown to result in markedly reduced release of LH in response to subsequent administration of the releasing hormone. Derivatives of cAMP exerted neither an inhibitory nor a stimulatory effect on desensitization. Nonreceptor mediated secretagogues (phorbol dibutyrate and melittin) promoted gonadotropin release without desensitizing pituitary cells indicating that release and desensitization are dissociable. However, conditions that promote GnRH receptor-receptor cross-linking did lead to reduced GnRH-responsiveness, even when the receptor was occupied by an antagonist. Cells were perifused with a conjugate consisting of two dimers of a pure GnRH-antagonist (D-pGlu¹-D-Phe²-D-Trp³-D-Lys⁶-GnRH) attached to cross-reacting antibody. The antagonist conjugate, now able to cross-link (microaggregate) GnRH receptors, is converted to an agonist. In the present work we show that the conjugate stimulates desensitization in addition to release of LH. This observation suggests that microaggregation is the final step common to both pathways, on the one hand leading to Ca²⁺ mobilization and release of LH, and on the other, leading to Ca²⁺ independent receptor-mediated desensitization. (Endocrinology 114: 553, 1984)

Footnotes

^* Supported by NIH Grants 13220 and HD-00337 and the Mellon Foundation.

Received March 7, 1983.

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