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Expression of Serotonin₇ Receptor and Coupling of Ectopic Receptors to Protein Kinase A and Ionic Currents in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome

Institut National de la Santé et de la Recherche Médicale (INSERM) Unite 413 (E.L., V.C., D.C., C.D., H.V., H.L.), Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, 76821 Mont-Saint-Aignan, France; Department of Endocrinology (L.G., J.B.), Centre Hospitalier Universitaire Cochin & Institut Cochin, INSERM Unite 567, Centre National de la Recherche Scientifique UMR8104, Institut Fédératif de Recherche 116, Université Paris V, René Descartes, 75014 Paris, France; and Department of Endocrinology (G.B.), Centre Hospitalier d’Orléans, 45067 Orléans, France

Address all correspondence and requests for reprints to: Dr. Hervé Lefebvre, IFRMP 23, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite 413, Department of Endocrinology, Hospital of Boisguillaume, Centre Hospitalier Universitaire of Rouen, 76031 Rouen Cedex, France. E-mail: herve.lefebvre{at}chu-rouen.fr.

Context: In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing’s syndrome, cortisol secretion is controlled by illegitimate membrane receptors.

Objective: The aim of the present study was to characterize the pharmacological properties and the transduction mechanisms of illegitimate receptors, i.e. receptors for serotonin (5-HT), gastric inhibitory polypeptide (GIP), and LH/human chorionic gonadotropin (hCG), expressed by AIMAH tissues to evaluate the role of ectopic receptors in the physiopathology of Cushing’s syndrome.

Design: We used in vitro studies on cultured adrenal hyperplasia cells.

Setting: The setting was a university research laboratory.

Patients: AIMAH tissues (H1–H3) were removed from three patients previously screened for illegitimate receptors.

Main Outcome Measure(s): The main outcome measures were steroidogenic and electrical activities of cultured adrenal hyperplasia cells.

Results: In vitro studies showed that the corticotropic effect of 5-HT was mediated by ectopic 5-HT₇ receptors in H1 and H2. GIP and hCG stimulated cortisol production via activation of cAMP-dependent protein kinase A in H2. On the contrary, the protein kinase A inhibitor H-89 did not affect hCG-induced cortisol production in H3. Activation of 5-HT₇ or GIP receptors enhanced T-type calcium current in H1 or H2 and H3, respectively. In addition, GIP reduced the amplitude of transient and sustained potassium currents in H2. Conversely, hCG did not modify T-type calcium current in H3.

Conclusions: These data show that, besides their coupling to the cAMP pathway, illegitimate adrenal receptors can activate additional transduction mechanisms, including modulation of membrane channels.

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				E Louiset, K Isvi, J M Gasc, C Duparc, B Cauliez, A Laquerriere, J M Kuhn, and H Lefebvre Ectopic expression of serotonin7 receptors in an adrenocortical carcinoma co-secreting renin and cortisol Endocr. Relat. Cancer, December 1, 2008; 15(4): 1025 - 1034. [Abstract] [Full Text] [PDF]

				E Louiset, V Contesse, L Groussin, D Cartier, C Duparc, V Perraudin, J Bertherat, and H Lefebvre Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing's syndrome: molecular, immunohistochemical and pharmacological correlates J. Endocrinol., January 1, 2008; 196(1): 1 - 9. [Abstract] [Full Text] [PDF]