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Regulation of the GABA_A Receptor by Nitric Oxide in Frog Pituitary Melanotrophs¹

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, 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, INSERM U-413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: hubert.vaudry{at}univ-rouen.fr

Nitric oxide (NO) is implicated in the regulation of various endocrine functions, but the effect of NO on GABA_A receptor transmission has never been reported in endocrine cells. In the present study, we have investigated the effects of various agents acting on the NO transduction pathway on GABA_A receptor function in frog pituitary melanotrophs. Histochemical studies using the NADPH-diaphorase reaction and immunohistochemical labeling with antibodies against neuronal NO synthase (nNOS) revealed that nNOS is expressed in the intermediate lobe of the pituitary and in cultured melanotrophs. Whole-cell patch-clamp recordings showed that the specific substrate of NOS L-arginine (L-Arg, 10^-4 M) or the NO donor sodium nitroprusside (10^-5 M) provoked a long-lasting inhibition of the current evoked by GABA (5 x 10^-6 M). The NOS inhibitor L-nitroarginine (10^-5 M) produced a biphasic effect, i.e. a transient decrease followed by a delayed increase of the GABA-evoked current amplitude. Similarly, the specific nNOS inhibitor 7-nitroindazole and the specific inducible NOS (iNOS) inhibitor aminoguanidine (10^-5 M each) provoked a transient depression of the current followed by a sustained potentiation. Formation of cGMP in neurointermediate lobes was enhanced by L-Arg (10^-4 M) and by the calcium-releasing agent caffeine (10^-4 M), and inhibited by the calmodulin (CaM)/Ca²⁺ complex blocker W7 (10^-5 M). The GABA-evoked current was potentiated by the guanylyl cyclase inhibitor ODQ (10^-8–10^-7 M) and inhibited by the protein kinase G (PKG) activator 8pCPT-cGMP (3 x 10^-7–3 x 10^-5 M). The present data indicate that NO, produced by a CaM/Ca²⁺-dependent NOS in frog melanotrophs, exerts an autocrine inhibitory effect on the GABA-evoked current. The action of NO on the GABA_A receptor function is mediated through activation of the cGMP/PKG pathway.

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