Julie Le Mestre1, Céline Duparc1, Yves Reznik2, Fidéline Bonnet-Serrano3,4, Philippe Touraine5, Olivier Chabre6, Jacques Young7, Mari Suzuki8, Mathilde Sibony4,9, Françoise Gobet10, Constantine A Stratakis8, Gérald Raverot11, Jérôme Bertherat4,12, Hervé Lefebvre1,13, Estelle Louiset1. 1. Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Normandie University, UNIROUEN, INSERM, U1239, Rouen, France. 2. Department of Endocrinology-Diabetology, Caen University Hospital, Caen, France. 3. Hormonal Biology Laboratory, Assistance Publique des Hôpitaux de Paris (AP-HP), Cochin Hospital, Paris, France. 4. Institut Cochin, INSERMU1016, CNRSUMR8104, Université Paris Descartes, Paris, France. 5. Department of Endocrinology and Reproductive Medicine, AP-HP, Pitié-Salpêtrière Hospital, Paris, France. 6. Department of Endocrinology, Diabetes and Nutrition, INSERM, U1036, Grenoble-Alpes University Hospital, Grenoble, France. 7. Department of Endocrinology and Reproductive Medicine, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France. 8. Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland. 9. Department of Pathology, AP-HP, Cochin Hospital, Paris, France. 10. Department of Pathology, Rouen University Hospital, Rouen, France. 11. Department of Endocrinology, Hospices Civils de Lyon, Groupement Hospitalier Est, Bron, France. 12. Department of Endocrinology, AP-HP, Cochin Hospital, Paris, France. 13. Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen University Hospital, Rouen, France.
Abstract
CONTEXT: In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. OBJECTIVE: To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. METHODS: Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. RESULTS: TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. CONCLUSION: Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.
CONTEXT: In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. OBJECTIVE: To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. METHODS: Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. RESULTS: TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. CONCLUSION: Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.
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