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Overexpression of Serotonin₄ Receptors in Cisapride-Responsive Adrenocorticotropin-Independent Bilateral Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome

European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), Laboratory of Cellular and Molecular Neuroendocrinology (D.C., I.L., J.-M.K., H.V., H.L.), Institut National de la Santé et de la Recherche Médicale (INSERM) U413, UA Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France; Laboratory of Oncologic Genetics (F.P., C.B.), Centre Henri Becquerel, 76038 Rouen, France; Department of Endocrinology (J.B.), Centre Hospitalier Universitaire (CHU) Cochin, 75031 Paris, France; Department of Endocrinology (P.C.), CHU of Toulouse, 31403 Toulouse, France; Department of Endocrinology (H.L., J.-M.K.), INSERM U413, CHU of Rouen, 76031 Rouen, France; Division of Endocrinology (A.L.), Department of Medicine, Research Center Hôtel-Dieu, CHUM, Montréal, Canada H2W 1T8; Department of Endocrinology (A.T.), CHU of Bordeaux, 33604 Bordeaux, France; and Department of Endocrinology (J.Y.), CHU Kremlin-Bicêtre, 94275 Le Kremlin Bicêtre, France

Address all correspondence and requests for reprints to: Dr. Hervé Lefebvre, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, Department of Endocrinology, Institut National de la Santé et de la Recherche Médicale U413, Hospital of Boisguillaume, Centre Hospitalier Universitaire of Rouen, 76031 Rouen Cedex, France. E-mail: herve.lefebvre{at}chu-rouen.fr.

The serotonin₄ (5-HT₄) receptor agonists cisapride and/or metoclopramide have been shown to stimulate cortisol secretion in some patients with ACTH-independent bilateral macronodular adrenal hyperplasias (AIMAH) causing Cushing’s syndrome. In the present study, we have investigated quantitatively and qualitatively the expression of the 5-HT₄ receptor in both normal adrenal cortex and tissues removed from six patients (P1–P6) with cisapride-responsive AIMAH and Cushing’s syndrome. Real-time quantitative PCR assay revealed that the 5-HT₄ receptor was overexpressed in four of the six hyperplasias studied when compared with normal adrenal cortex. In these tissues, 5-HT₄ receptor mRNA expression was 3 to 16 times higher than in normal glands, likely explaining the abnormal in vivo cortisol response to cisapride. Characterization of 5-HT₄ receptor splice variants by RT-PCR in both hyperplastic and normal adrenals showed that the variants present in the two hyperplasias that did not overexpress the 5-HT₄ receptor, i.e. P2 and P5, could also be detected in the normal adrenal tissue. In addition, sequencing of the full-length cDNAs encoding 5-HT₄ receptors in hyperplasias P2 and P5 did not reveal any mutation. Taken together, our results show an overexpression of the 5-HT₄ receptor in cisapride-responsive AIMAH. However, in two cases, the level of expression of the receptor in the hyperplastic adrenal cortex was similar to that of normal adrenal gland. The enhanced sensitivity of these two tissues to 5-HT₄ receptor agonists was not due to ectopic expression of 5-HT₄ receptor isoforms or to the occurrence of somatic gain-of-function mutation of the receptor.

This work was supported by the Conseil Régional de Haute-Normandie, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, Institut National de la Santé et de la Recherche Médicale U413, Centre Hospitalier Universitaire de Rouen, the Réseau COMETE (PHRC AOM 95201), and the Canadian Institutes of Health Research (Grant MT-13189, to A.L.).

Abbreviations: AIMAH, ACTH-independent bilateral macronodular adrenal hyperplasias; CT, computerized tomography; 5-HT, serotonin; LVP, lysine vasopressin; nts, nucleotides; PBGD, porphobilinogen deaminase.

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