An Autocrine Switch Governing Pulsatile Secretion

Abstract

Episodic secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons is required for normal gonadal function. GnRH release depends on the intracellular calcium concentration [Ca 2+ ] 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 α 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 α subunits. GnRH decreased membrane-associated Gα q/11 subunits (indicative of Gα q/11 activation) and stimulated a dose-dependent increase in inositol bisphosphate and inositol trisphosphate production and in [Ca 2+ ] i , whereas GnRH antagonists, which increased membrane-associated Gα 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 Gα s and Gα i were stimulated at low concentrations of GnRH but only Gα i was stimulated at high concentrations. The authors developed a model in which low concentrations of GnRH, acting through Gα s and Gα q/11 , increase [Ca 2+ ] i , stimulate production of cAMP, and stimulate GnRH secretion, until extracellular GnRH concentrations become high enough to trigger the switch to Gα 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]