ECE2017 Guided Posters Adrenal 2 (10 abstracts)
Activation of the cAMP/PKA transduction system triggers abnormal expression of the serotonin signaling pathway in human adrenocortical cells
Julie Le Mestre 1 , Céline Duparc 1 , Zakariae Bram 1 , Yves Reznik 2 , Jérôme Bertherat 3 , Philippe Touraine 4 , Jacques Young 5 , Olivier Chabre 6 , Constantine A. Stratakis 7 , Hervé Lefebvre 1, & Estelle Louiset 1
1Normandie University, UNIROUEN, INSERM, U1239, Rouen, France; 2Department of Endocrinology-Diabetology, Caen University Hospital, Caen, France; 3Department of Endocrinology and Metabolic Diseases, Assistance Publique des Hôpitaux de Paris, Hôpital Cochin, Paris, France; 4Department of Endocrinology and Reproductive Medicine, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France; 5Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Kremlin-Bicêtre, France; 6Department of Endocrinology, CHU de Grenoble, Grenoble, France; 7Section of Endocrinology and Genetics, PDEGEN, NICHD, Bethesda, Maryland, USA; 8Department of Endocrinology, Rouen University Hospital, Rouen, France.
In human adrenals, serotonin (5-HT), released by subcapsular mast cells, increases aldosterone secretion through activation of type 4 serotonin receptors (5-HT4R) but only exerts a modest control on cortisol production. Interestingly, illicit synthesis of 5-HT in adrenocortical cells as well as overexpression of the 5-HT4R and ectopic expression of the type 7 receptor (5-HT7R) have been observed in bilateral macronodular adrenal hyperplasia responsible for hypercortisolism. In this study, we have investigated the expression of the key enzyme of 5-HT synthesis tryptophan hydroxylase (Tph) and 5-HT4R, 5-HT6R, 5-HT7R in the adrenal samples removed from patients suffering from diseases associated with activation of the cAMP/PKA pathway in adrenocortical cells, such as primary pigmented nodular adrenocortical disease (PPNAD), Cushing’s disease (CD), ectopic secretion of ACTH, and 21-hydroxylase deficiency (21-OHD), in comparison with normal adrenals. In PPNAD cells, we observed upregulation of Tph together with 5-HT4R, 5-HT6R and 5-HT7R. Overexpression of the 5-HT signaling pathway appeared to be the consequence of the activation of PKA by PRKAR1A gene mutations which cause the disease. 5-HT strongly stimulated cortisol production and inhibition of Tph reduced corticosteroidogenesis in cultured PPNAD cells. High expression of Tph and 5-HTRs was also detected in adrenal tissues exposed to high plasma ACTH levels, including CD, 21-OHD and ectopic Cushing’s syndrome. Our results indicate that activation of the cAMP/PKA pathway in adrenocortical cells resulting either from PRKAR1A mutations or activation of the MC2R by sustained increase in plasma ACTH levels induces an aberrant serotonergic stimulatory loop in zona fasciculata. They also suggest that the intraadrenal 5-HT signaling pathway may participate in the pathophysiology of PPNAD-associated and ACTH-dependent hypercortisolisms and could represent an adaptive mechanism to increase glucocorticoid synthesis in 21-hydroxylase deficiency.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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