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Involvement of Protein Kinase C and Protein Tyrosine Kinase in Thyrotropin-Releasing Hormone-Induced Stimulation of -Melanocyte-Stimulating Hormone Secretion in Frog Melanotrope Cells¹

European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale (INSERM U 413), Unité Affiliée au Centre National de la Recherche Scientifique (UA CNRS), University of Rouen (L.G., M.L., M.G., M.C.T., H.V.), 76821 Mont-Saint-Aignan, France; and Department of Cellular Animal Physiology, Nijmegen Institute for Neurosciences, University of Nijmegen (E.W.R.), Toernooiveld 1, 6525 ED, Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Hubert Vaudry, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U 413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: hubert.vaudry{at}univ-rouen.fr

We have previously shown that the stimulatory effect of TRH on -MSH secretion from the frog pars intermedia is associated with Ca²⁺ influx through voltage-dependent Ca²⁺ channels, activation of a phospholipase C and mobilization of intracellular Ca²⁺ stores. The aim of the present study was to investigate the contribution of protein kinase C (PKC), adenylyl cyclase (AC), Ca²⁺/calmodulin-dependent protein kinase II (CAM KII), phospholipase A₂, and protein tyrosine kinase (PTK) in TRH-induced -MSH release. Incubation of frog neurointermediate lobes (NILs) with phorbol 12-myristate-13-acetate (24 h), which causes desensitization of PKC, or with the PKC inhibitor NPC-15437, reduced by approximately 50% of the effect of TRH on -MSH release. In most melanotrope cells, TRH induces a sustained and biphasic increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_i). Preincubation with phorbol 12-myristate-13-acetate or NPC-15437 suppressed the plateau phase of the Ca²⁺ response. Incubation of NILs with TRH (10^-6 M; 20 min) had no effect on cAMP production. In addition, the AC inhibitor SQ 22,536 did not affect the secretory response of NILs to TRH. These data indicate that the phospholipase C/PKC pathway, but not the AC/protein kinase A pathway, is involved in TRH-induced -MSH release. The calmodulin inhibitor W-7 and the CAM KII inhibitor KN-93 did not significantly reduce the response to TRH. Similarly, the phospholipase A₂ inhibitors quinacrine and 7–7'-DEA did not impair the effect of TRH on -MSH secretion. The PTK inhibitors ST638 and Tyr-A23 had no effect on TRH-induced [Ca²⁺]_i increase but inhibited in a dose-dependent manner TRH-evoked -MSH release (ED₅₀= 1.22 x 10^-5 M and ED₅₀= 1.47 x 10^-5 M, respectively). Taken together, these data indicate that, in frog melanotrope cells, PKC and PTK are involved in TRH-induced -MSH secretion. Activation of PKC is responsible for the sustained phase of the increase in [Ca²⁺]_i, whereas activation of PTK does not affect Ca²⁺ mobilization.

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