In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 100, No. 5 ( 2003-03-04), p. 2969-2974
Kurzfassung:
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 G q/11 as indicated by release of membrane-bound α q/11 subunits and increased inositol phosphate/Ca 2+ signaling. Conversely, GnRH antagonists increase membrane-associated α q/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 G i . Coupling of the agonist-activated GnRH-R to both G s and G i proteins was demonstrated by the ability of nanomolar GnRH concentrations to reduce membrane-associated α s and α i3 levels and of higher concentrations to diminish α i3 levels. Conversely, α i3 was increased during GnRH antagonist and pertussis toxin treatment, with concomitant loss of pulsatile GnRH secretion. In cholera toxin-treated GnRH neurons, decreases in α s 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 Ca 2+ signaling via G s -cAMP stimulatory and G i -cAMP inhibitory mechanisms. Activation of G i 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 Ca 2+ - and cAMP-dependent signaling and GnRH neuronal firing.
Materialart:
Online-Ressource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0535708100
Sprache:
Englisch
Verlag:
Proceedings of the National Academy of Sciences
Publikationsdatum:
2003
ZDB Id:
209104-5
ZDB Id:
1461794-8
SSG:
11
SSG:
12
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