PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease

Bram, Zakariae; Louiset, Estelle; Ragazzon, Bruno; Renouf, Sylvie; Wils, Julien; Duparc, Céline; Boutelet, Isabelle; Rizk-Rabin, Marthe; Libé, Rossella; Young, Jacques; Carson, Dennis; Vantyghem, Marie-Christine; Szarek, Eva; Martinez, Antoine; Stratakis, Constantine A.; Bertherat, Jérôme; Lefebvre, Henri

doi:10.1172/jci.insight.87958

Cited by 29 publications

(25 citation statements)

References 60 publications

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“…In a recent report, Bram et al [7] have demonstrated that, like other neuroendocrine markers, serotonin (5-HT) is abundantly produced in the adrenal gland of patients with PPNAD. 5-HT stimulates glucocorticoid production by increasing the expression of CYP11B1 mRNA an essential enzyme in cortisol synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular genetic analysis of the PRKAR1A gene identified the heterozygous hotspot deletion c.709-7_709-2del6 in intron 7 [7, 9, 13, 17]. Further investigations were performed to rule out other features of CNC.…”

Section: Methodsmentioning

confidence: 99%

“…PPNAD is a rare genetic disease that may be isolated (12% of cases) but mostly associated with myxomas, lentigines, and multiple endocrine gland disorders, integrating an autosomal dominant disorder known as the Carney complex (CNC), caused by germline mutations of the regulatory subunit type 1A (RIα) of cAMP-dependent protein kinase ( PRKAR1A ) gene [1, 3, 6, 7]. The mutation detection rate was 41% in the CNC phenotype [8] and up to 82% for patients with PPNAD [9, 10].…”

Section: Introductionmentioning

confidence: 99%

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Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

et al. 2018

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Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

et al. 2018

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“…In the opposite, the involvement of 5-HT in the control of adrenal steroidogenesis has been extensively documented. First, it has been demonstrated that human mast cells express tryptophan hydroxylase type 1 (Tph1), the rate-limiting enzyme synthesizing 5-HT from tryptophan [47]. Second, the presence of 5-HT in adrenal mast cells has been evidenced by histological studies [28,47].…”

Section: Serotonin Secreted By Mast Cells Stimulates Aldosterone Syntmentioning

confidence: 99%

Role of Mast Cells in the Control of Aldosterone Secretion

et al. 2020

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Mast cells are immune cells present in adrenals from various species. Proliferation and activation of adrenal mast cells seem to be influenced by environment, since they increase during summer and in response to sodium restriction in frogs and mouse, respectively. Although the physiological factors regulating adrenal mast cell activity have not been identified, they might involve neurotransmitters and the renin-angiotensin system. Some data indicate that adrenal mast cells stimulate proliferation of steroidogenic cells in the zona glomerulosa and activate the mineralocorticoid production. In human, mast cell degranulation stimulates aldosterone synthesis through the release of serotonin (5-HT) and activation of 5-HT4 receptors. Increase in mast cell population and upregulation of the 5-HT signaling pathway occur in aldosterone-producing adenomas. In particular, aldosterone-producing adenoma cells overexpress 5-HT4 receptors and are hyper-responsive to 5-HT4 receptor agonists. These data suggest that the intra-adrenal serotonergic regulatory system represents a potential target for development of both adrenal imaging methods to evaluate the lateralization of aldosterone production, and pharmacological treatments of primary aldosteronism.

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“…In this rodent, the action of 5-HT on aldosterone secretion is mediated by 5-HT 7 receptors (Lenglet et al, 2002). Our previous studies have demonstrated that 5-HT 7 receptor is not expressed in normal human adrenocortical cells (Bram et al, 2016; Louiset et al, 2006), while abnormal expression of functional 5-HT 7 receptors has been detected in adrenal neoplasia from patients with primary hypercortisolism (Bram et al, 2016; Louiset et al, 2008, 2006). These data demonstrate that expression pattern of 5-HT receptor subtypes varies in a species-specific manner or between physiological and pathophysiological conditions.…”

Section: Discussionmentioning

confidence: 99%

Role of cAMP/PKA pathway and T-type calcium channels in the mechanism of action of serotonin in human adrenocortical cells

Louiset

Duparc

Lenglet

et al. 2017

Molecular and Cellular Endocrinology

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In human adrenal, serotonin (5-HT), produced by mast cells located in zona glomerulosa, stimulates production of corticosteroids through a paracrine mechanism involving the 5-HT receptor type 4 (5-HT4). The aim of the present study was to investigate the transduction mechanisms associated with activation of 5-HT4 receptors in human adrenocortical cells. Our results show that 5-HT4 receptors are present in the outer adrenal cortex, both in glomerulosa and fasciculata zonae. In the zona glomerulosa. 5-HT4 receptor was detected both in immunopositive and immunonegative cells for 11β-hydroxylase, an enzyme involved in cortisol synthesis. The data demonstrate that 5-HT4 receptors are positively coupled to adenylyl cyclases and cAMP-dependent protein kinases (PKA). The activation of the cAMP-PKA pathway is associated with calcium influx through T-type calcium channels. Both the adenylyl cyclase/PKA pathway and the calcium influx are involved in 5-HT-induced cortisol secretion.

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PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease

Cited by 29 publications

References 60 publications

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

Role of Mast Cells in the Control of Aldosterone Secretion

Role of cAMP/PKA pathway and T-type calcium channels in the mechanism of action of serotonin in human adrenocortical cells

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