Activation of the cAMP/PKA transduction system triggers abnormal expression of the serotonin signaling pathway in human adrenocortical cells. - Archive ouverte HAL
Poster De Conférence Année : 2017

Activation of the cAMP/PKA transduction system triggers abnormal expression of the serotonin signaling pathway in human adrenocortical cells.

Résumé

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. DOI: 10.1530/endoabs.49.GP12
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Dates et versions

hal-02396867 , version 1 (06-12-2019)

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  • HAL Id : hal-02396867 , version 1

Citer

Julie Le Mestre, Céline Duparc, Yves Reznik, Jérôme Bertherat, Philippe Touraine, et al.. Activation of the cAMP/PKA transduction system triggers abnormal expression of the serotonin signaling pathway in human adrenocortical cells.. 19th European Congress of Endocrinology 2017, May 2017, Lisbon, Portugal. ECE 2017 ABSTRACT BOOK, 49, pp.GP12, 2017. ⟨hal-02396867⟩
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