title: Gamma-aminobutyric acid B receptor mediated inhibition of gonadotropin-releasing hormone neurons is suppressed by kisspeptin-G protein-coupled receptor 54 signaling.
abstract: Gamma-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 G alpha(i,o)-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 17beta-estradiol as compared with oil vehicle did not significantly alter either the EC(50) for the baclofen-induced response (0.8 +/- 0.1 vs. 1.0 +/- 0.1 microM, respectively) or the 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 G alpha(q)-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.
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Zhang
authors.forename: Martha A
authors.initials: MA
authors.lastname: Bosch
authors.forename: Oline K
authors.initials: OK
authors.lastname: Rønnekleiv
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D059648:Kisspeptins; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010721:Phosphinic Acids / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D018080:Receptors, GABA-B / Q000502:physiology*; D000074502:Receptors, Kisspeptin-1; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000494:pharmacology / Q000502:physiology*
chemical_list: D001596:Benzylamines; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D010721:Phosphinic Acids; D043562:Receptors, G-Protein-Coupled; D018080:Receptors, GABA-B; D000074502:Receptors, Kisspeptin-1; D025521:Tumor Suppressor Proteins; C083008:CGP 52432; D007987:Gonadotropin-Releasing Hormone; D001418:Baclofen