G PROTEINS An Autocrine Switch Governing Pulsatile Secretion

Episodic secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons is required for normal gonadal function. GnRH release depends on the intracellular calcium concentration [Ca²⁺]_i and is sensitive to adenosine 3',5'-monophosphate (cAMP). The mechanisms governing pulsatile secretion, however, have remained unclear, although an autocrine contribution from GnRH itself has been postulated. Krsmanovic et al. investigated coupling of the GnRH receptor (GnRHR), which stimulates several heterotrimeric guanosine triphosphate (GTP)-binding protein (G protein)-mediated pathways, to various G protein subunits and implicated a GnRH-induced switch in coupling in the pulsatile secretion of GnRH. The authors used Western analysis of rat primary hypothalamic neurons or immortalized GnRH neurons to monitor membrane association of different G protein subunits. GnRH decreased membrane-associated G_q/11 subunits (indicative of G_q/11 activation) and stimulated a dose-dependent increase in inositol bisphosphate and inositol trisphosphate production and in [Ca²⁺]_i , whereas GnRH antagonists, which increased membrane-associated G_q/11, abolished pulsatile secretion. GnRH had a biphasic effect on cAMP production, stimulating production at nanomolar concentrations but inhibiting it at micromolar concentrations. Pharmacological analysis combined with selective G protein subunit overexpression indicated that both G_s and G_i were stimulated at low concentrations of GnRH but only G_i was stimulated at high concentrations. The authors developed a model in which low concentrations of GnRH, acting through G_s and G_q/11, increase [Ca²⁺]_i, stimulate production of cAMP, and stimulate GnRH secretion, until extracellular GnRH concentrations become high enough to trigger the switch to G_i coupling. Elevated GnRH leads to decreased cAMP production and consequently less GnRH secretion, thereby reactivating the stimulatory cycle.

L. Z. Krsmanovic, N. Mores, C. E. Navarro, K. K. Arora, K. J. Catt, An agonist-induced switch in G protein coupling of the gonadotropin-releasing hormone receptor regulates pulsatile neuropeptide secretion. Proc. Natl. Acad. Sci U.S.A. 111, 2969-2974 (2003). [Abstract] [Full Text]

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VIRTUAL JOURNAL
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 (4 March 2003)
PNAS 100 (5), 2969. [DOI: 10.1073/pnas.0535708100]
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