γ-aminobutyric acid B receptor mediated inhibition of gonadotropin-releasing hormone neurons is suppressed by kisspeptin-G protein-coupled receptor 54 signaling

Chunguang Zhang, Martha A. Bosch, Oline K. Rønnekleiv, Martin J. Kelly

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

γ-Aminobutyric acid (GABA) is one of the most important neurotransmitters that regulate the excitability of GnRH neurons. Numerous studies have shown that GABA activates Cl - currents in GnRH neurons, and these effects are antagonized by GABA A receptor antagonists. The GABA B receptor is a heterodimer composed of GABA B R1 and R2, and although both subunits have been localized in GnRH neurons, nothing is known about the cellular signaling of this Gaio-coupled receptor in GnRH neurons. Using whole-cell recordings from mouse enhanced green fluorescent protein-GnRH neurons, we found that the GABA B receptor agonist baclofen hyperpolarized GnRH neurons through activation of an inwardly rectifying K + current in a concentration-dependent manner. The effects of baclofen were antagonized by the selective GABA B receptor antagonist CGP 52432 with a K i (inhibitory constant) of 85 nm. Furthermore, in the presence of the GABA A receptor antagonist picrotoxin, GABA hyperpolarized GnRH neurons in a similar manner. Treatment with 17β-estradiol as compared with oil vehicle did not significantly alter either the EC50 for the ba- clofen-induced response (0.8 ± 0.1 vs. 1.0 ± 0.1 μm, respectively) orthe maximal outward current (10.8 ± 1.7 pA vs. 11.4 ± 0.6 pA, respectively) in GnRH neurons. However, the outward current (and membrane hyperpolarization) was abrogated by submaximal concentrations of the G protein- coupled receptor 54 (GPR54) agonist kisspeptin-10 in both groups, indicating that Gaq-coupled (GPR54) can desensitize the GABA B receptor-mediated response. Therefore, the activation of GABA B receptors in GnRH neurons may provide increased inhibitory tone during estrogen-negative feedback states that is attenuated by kisspeptin during positive feedback.

Original languageEnglish (US)
Pages (from-to)2388-2394
Number of pages7
JournalEndocrinology
Volume150
Issue number5
DOIs
StatePublished - May 1 2009

ASJC Scopus subject areas

  • Endocrinology

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