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-Aminobutyric Acid B Receptor Mediated Inhibition of Gonadotropin-Releasing Hormone Neurons Is Suppressed by Kisspeptin-G Protein-Coupled Receptor 54 Signaling

Departments of Physiology and Pharmacology (C.Z., M.B., O.K.R., M.J.K.) and Anesthesiology and Perioperative Medicine (O.K.R.) and Division of Neuroscience (O.K.R.), Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon 97239-3089

Address all correspondence and requests for reprints to: Oline K. Rønnekleiv or Martin J. Kelly, Department of Physiology and Pharmacology, Mail Code L334, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239. E-mail: ronnekle{at}ohsu.edu or kellym{at}ohsu.edu.

-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_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 17β-estradiol as compared with oil vehicle did not significantly alter either the EC₅₀ for the baclofen-induced response (0.8 ± 0.1 vs. 1.0 ± 0.1 µM, 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_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.

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