Abstract
Kisspeptin plays an important role in puberty and subsequent fertility by activating its receptor, G-protein-coupled receptor 54 (GPR54), and increasing cytoplasmic free Ca2+ concentration ([Ca2+]i) and gonadotropin-releasing hormone (GnRH) secretion in GnRH neurons. Yet the mechanism by which kisspeptin increases [Ca2+]i in GnRH neurons remains to be fully elucidated. In other neurons, voltage-gated Ca2+ channel (VGCC) activity has been shown to be inversely related to [Ca2+]i. We used whole-cell patch-clamp recording to examine the effects of kisspeptin-10 (KP-10) on VGCC activity evoked by step depolarizations in GnRH neurons in brain slices from pubertal male GnRH-green fluorescent protein transgenic mice. Prolonged (>30 s) KP-10 application inhibited Ca2+ currents. The GPR54 antagonist peptide 234, chelation of intracellular Ca2+ by 1,2-bis(2-aminophenoxy)ethane N,N,N′,N′-tetraacetic acid, substitution of Ba2+ for Ca2+, the calmodulin antagonists calmidazolium and trifluoperazine, the phospholipase C inhibitor edelfosine, the canonical transient receptor potential (TRPC) channel and inositol 1,4,5-trisphosphate receptor (IP3R) antagonist 2-APB, the TRPC channel antagonist BTP2 and the endoplasmic reticulum Ca2+-ATPase blocker cyclopiazonic acid each prevented inhibition. The IP3R antagonists caffeine (10 µM), heparin and intracellular 2-APB prevented inhibition to a lesser extent. The ryanodine receptor (RyR) antagonists ryanodine and dantrolene prevented inhibition, and the RyR agonist caffeine (30 mM) mimicked the effects of KP-10 on Ca2+ currents. Our results suggest that kisspeptin induces Ca2+ influx through TRPC channels and Ca2+ release via IP3Rs and RyRs, and that this is followed by Ca2+/CaM-dependent inhibition of VGCCs.
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2012
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