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Neurotensin Stimulates Both Calcium Mobilization from Inositol Trisphosphate-Sensitive Intracellular Stores and Calcium Influx through Membrane Channels in Frog Pituitary Melanotrophs

European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale, Unité-413, University of Rouen, 76821 Mont-Saint-Aignan, France

Address all correspondence and requests for reprints to: Dr. Hubert Vaudry, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale, Unité-413, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: hubert.vaudry{at}univ-rouen.fr.

Neurotensin (NT) is a potent stimulator of electrical and secretory activities in frog pituitary melanotrophs. The aim of the present study was to characterize the transduction pathways associated with activation of NT receptors in frog melanotrophs. Application of synthetic frog NT (fNT) increased the cytosolic calcium concentration ([Ca²⁺]_c) and stimulated the formation of inositol trisphosphate (IP₃). The phospholipase C inhibitor U-73122 blocked the electrophysiological and secretory effects of fNT. Intracellular application of the IP₃ receptor antagonist heparin abolished fNT-induced electrical activity. Suppression of Ca²⁺ in the incubation medium markedly reduced the effect of NT on [Ca²⁺]_c, firing rate, and -melanocyte-stimulating hormone (MSH) secretion. Similarly, the inhibitor of IP₃-induced Ca²⁺ release and store-operated Ca²⁺ channels, 2-Aminoethoxydiphenylborane, and the nonselective Ca²⁺ channel blockers GdCl₃ and NiCl₂, attenuated the [Ca²⁺]_c increase and the electrical and secretory responses evoked by fNT. Coapplication of the L- and N-type Ca²⁺ channel blockers nifedipine and -CgTx GVIA reduced the effects of fNT on action potential discharge, [Ca²⁺]_c increase, and MSH release. The protein kinase C (PKC) inhibitors, PKC-(19–31) and chelerythrine, reduced the electrophysiological and secretory responses induced by iterative applications of fNT. Collectively, these results demonstrate that, in frog melanotrophs, NT stimulates the phospholipase C/PKC pathway and increases [Ca²⁺]_c. Both Ca²⁺ release from intracellular stores and Ca²⁺ influx through L- and N-type Ca²⁺ channels are involved in fNT-induced MSH secretion. In addition, the present data indicate that PKC plays a crucial role in maintenance of the responsiveness of melanotrophs to NT.

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