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Kisspeptin-10 Facilitates a Plasma Membrane-Driven Calcium Oscillator in Gonadotropin-Releasing Hormone-1 Neurons

Cellular and Developmental Neurobiology Section (S.C., C.S.C., S.W.), National Institute of Neurological Disorder and Stroke/National Institutes of Health, and Section on Cellular Signaling (S.S.), Program in Developmental Neuroscience/National Institute of Child Health and Human Development/National Institutes of Health, Bethesda Maryland 20892; and Centre for Neuroendocrinology (S.C.), Department of Physiology, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand

Address all correspondence and requests for reprints to: Susan Wray, Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorder and Stroke/National Institutes of Health, Bethesda, Maryland 20892. E-mail: wrays{at}ninds.nih.gov.

Kisspeptins, the natural ligands of the G-protein-coupled receptor (GPR)-54, are the most potent stimulators of GnRH-1 secretion and as such are critical to reproductive function. However, the mechanism by which kisspeptins enhance calcium-regulated neuropeptide secretion is not clear. In the present study, we used GnRH-1 neurons maintained in mice nasal explants to examine the expression and signaling of GPR54. Under basal conditions, GnRH-1 cells exhibited spontaneous baseline oscillations in intracellular calcium concentration ([Ca²⁺]_i), which were critically dependent on the operation of voltage-gated, tetrodotoxin (TTX)-sensitive sodium channels and were not coupled to calcium release from intracellular pools. Activation of native GPR54 by kisspeptin-10 initiated [Ca²⁺]_i oscillations in quiescent GnRH-1 cells, increased the frequency of calcium spiking in oscillating cells that led to summation of individual spikes into plateau-bursting type of calcium signals in a subset of active cells. These changes predominantly reflected the stimulatory effect of GPR54 activation on the plasma membrane oscillator activity via coupling of this receptor to phospholipase C signaling pathways. Both components of this pathway, inositol 1,3,4-trisphosphate and protein kinase C, contributed to the receptor-mediated modulation of baseline [Ca²⁺]_i oscillations. TTX and 2-aminoethyl diphenylborinate together abolished agonist-induced elevation in [Ca²⁺]_i in almost all cells, whereas flufenamic acid was less effective. Together these results indicate that a plasma membrane calcium oscillator is spontaneously operative in the majority of prenatal GnRH-1 neurons and is facilitated by kisspeptin-10 through phosphatidyl inositol diphosphate hydrolysis and depolarization of neurons by activating TTX-sensitive sodium channels and nonselective cationic channels.

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