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Endocrinology Vol. 141, No. 3 1083-1092
Copyright © 2000 by The Endocrine Society

ARTICLES

Subunit Composition and Pharmacological Characterization of {gamma}-Aminobutyric Acid Type A Receptors in Frog Pituitary Melanotrophs1

Estelle Louiset, Ruth McKernan, Werner Sieghart and Hubert Vaudry

European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U-413, Centre National de la Recherche Scientifique, University of Rouen (E.L., H.V.), 76821 Mont-Saint-Aignan, France; the Department of Biochemistry and Molecular Biology, Merck, Sharp, and Dohme Research Laboratories, Terlings Park (R.M.K.), Harlow, Essex, United Kingdom CM20 2QR; and the Section of Biochemical Psychiatry, University Clinic for Psychiatry (W.S.), A-1090 Vienna, Austria

Address all correspondence and requests for reprints to: Dr. E. Louiset, 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.

The frog pars intermedia is composed of a single population of endocrine cells directly innervated by {gamma}-aminobutyric acid (GABA)ergic nerve terminals. We have previously shown that GABA, acting through GABAA receptors, modulates both the electrical and secretory activities of frog pituitary melanotrophs. The aim of the present study was to take advantage of the frog melanotroph model to determine the relationship between the subunit composition and the pharmacological properties of native GABAA receptors. Immunohistochemical labeling revealed that in situ and in cell culture, frog melanotrophs were intensely stained with {alpha}2-, {alpha}3-, {gamma}2-, and {gamma}3-subunit antisera and weakly stained with a {gamma}1-subunit antiserum. Melanotrophs were also immunolabeled with a monoclonal antibody to the ß2/ß3-subunit. In contrast, frog melanotrophs were not immunoreactive for the {alpha}1-, {alpha}5-, and {alpha}6-isoforms. The effects of allosteric modulators of the GABAA receptor on GABA-activated chloride current were tested using the patch-clamp technique. Among the ligands acting at the benzodiazepine-binding site, clonazepam (EC50, 5 x 10-9 M), diazepam (EC50 , 10-8 M), zolpidem (EC50, 3 x 10-8 M), and ß-carboline-3-carboxylic acid methyl ester (EC50, 10-6 M) were found to potentiate the whole cell GABA-evoked current in a dose-dependent manner. Methyl-6,7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate (IC50, 3 x 10-5 M) inhibited the current, whereas Ro15–4513 had no effect. Among the ligands acting at other modulatory sites, etomidate (EC50, 2 x 10-6 M) enhanced the GABA-evoked current, whereas 4'-chlorodiazepam (IC50, 4 x 10-7 M), ZnCl2 (IC50, >5 x 10-5 M), and furosemide (IC50, >3 x 10-4 M) depressed the response to GABA. PK 11195 did not affect the GABA-evoked current or its inhibition by 4'-chlorodiazepam. The results indicate that the native GABAA receptors in frog melanotrophs are formed by combinations of {alpha}2-, {alpha}3-, ß2/3-, {gamma}1-, {gamma}2-, and {gamma}3-subunits. The data also demonstrate that clonazepam is the most potent, and zolpidem is the most efficient positive modulator of the native receptors. Among the inhibitors, 4'-chlorodiazepam is the most potent, whereas ZnCl2 is the most efficient negative modulator of the GABAA receptors. The present study provides the first correlation between subunit composition and the functional properties of native GABAA receptors in nontumoral endocrine cells.




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