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PNAS 100 (5): 2969-2974

Copyright © 2003 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / PHYSIOLOGY

An agonist-induced switch in G protein coupling of the gonadotropin-releasing hormone receptor regulates pulsatile neuropeptide secretion

Lazar Z. Krsmanovic, Nadia Mores*, Carlos E. Navarro, Krishan K. Arora, and Kevin J. Catt{dagger}

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4510

Received for publication September 19, 2002.

Abstract: The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from normal and immortalized hypothalamic GnRH neurons is highly calcium-dependent and is stimulated by cAMP. It is also influenced by agonist activation of the endogenous GnRH receptor (GnRH-R), which couples to Gq/11 as indicated by release of membrane-bound αq/11 subunits and increased inositol phosphate/Ca2+ signaling. Conversely, GnRH antagonists increase membrane-associated αq/11 subunits and abolish pulsatile GnRH secretion. GnRH also stimulates cAMP production but at high concentrations has a pertussis toxin-sensitive inhibitory effect, indicative of receptor coupling to Gi. Coupling of the agonist-activated GnRH-R to both Gs and Gi proteins was demonstrated by the ability of nanomolar GnRH concentrations to reduce membrane-associated αs and αi3 levels and of higher concentrations to diminish αi3 levels. Conversely, αi3 was increased during GnRH antagonist and pertussis toxin treatment, with concomitant loss of pulsatile GnRH secretion. In cholera toxin-treated GnRH neurons, decreases in αs immunoreactivity and increases in cAMP production paralleled the responses to nanomolar GnRH concentrations. Treatment with cholera toxin and 8-bromo-cAMP amplified episodic GnRH pulses but did not affect their frequency. These findings suggest that an agonist concentration-dependent switch in coupling of the GnRH-R between specific G proteins modulates neuronal Ca2+ signaling via Gs-cAMP stimulatory and Gi-cAMP inhibitory mechanisms. Activation of Gi may also inhibit GnRH neuronal function and episodic secretion by regulating membrane ion currents. This autocrine mechanism could serve as a timer to determine the frequency of pulsatile GnRH release by regulating Ca2+- and cAMP-dependent signaling and GnRH neuronal firing.

* On leave from the Department of Pharmacology, Catholic University of the Sacred Heart, 00168 Rome, Italy.

{dagger} To whom correspondence should be addressed at: Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 49, Room 6A-36, Bethesda, MD 20892-4510. E-mail: catt{at}helix.nih.gov.

Edited by Maria Iandolo New, Weill Medical College of Cornell University, New York, NY, and approved January 3, 2003

This paper was submitted directly (Track II) to the PNAS office.

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