Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels
| Autor: | Olivier Chabre, Céline Duparc, Mathilde Sibony, Mari Suzuki, Philippe Touraine, Fideline Bonnet-Serrano, Estelle Louiset, Constantine A. Stratakis, Françoise Gobet, Jacques Young, Julie Le Mestre, Hervé Lefebvre, Jérôme Bertherat, Yves Reznik, Gérald Raverot |
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| Přispěvatelé: | Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Service Endocrinologie - Diabétologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), National Institutes of Health [Bethesda] (NIH), Santé Lyon Est - Louis Léopold Ollier, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], Service d'Anatomie et cytologie pathologiques [CHU Tenon], DUPARC, Céline |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Endocrinology Diabetes and Metabolism Receptor expression Clinical Biochemistry Adrenal Gland Neoplasms Stimulation Tryptophan Hydroxylase Biochemistry Cushing syndrome 0302 clinical medicine Endocrinology Adrenal Glands Cyclic AMP Cushing Syndrome [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Chemistry Adrenal cortex Middle Aged [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism 3. Good health Up-Regulation medicine.anatomical_structure Female Signal Transduction Cortisol secretion Adenoma Adult medicine.medical_specialty Serotonin endocrine system Primary Cell Culture 030209 endocrinology & metabolism [SDV.BC]Life Sciences [q-bio]/Cellular Biology Serotonergic 03 medical and health sciences Adrenocorticotropic Hormone Internal medicine medicine [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Humans Pituitary ACTH Hypersecretion [SDV.BC] Life Sciences [q-bio]/Cellular Biology Clinical Research Articles Biochemistry (medical) medicine.disease Cushing Disease 030104 developmental biology Receptors Serotonin Steroid 21-Hydroxylase Protein Kinases |
| Zdroj: | Journal of Clinical Endocrinology and Metabolism Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2019, 104 (11), pp.4967-4980. ⟨10.1210/jc.2019-00425⟩ Journal of Clinical Endocrinology and Metabolism, 2019, 104 (11), pp.4967-4980. ⟨10.1210/jc.2019-00425⟩ J Clin Endocrinol Metab |
| ISSN: | 0021-972X 1945-7197 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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