ECE2024 Rapid Communications Rapid Communications 11: Adrenal and Cardiovascular Endocrinology | Part II (7 abstracts)
Modulation of calcium signaling on demand to decipher the molecular mechanisms of primary aldosteronism
Bakhta Fedlaoui 1 , Cosentino Teresa 1 , Al Sayed Zeina 1 , Giscos-Douriez Isabelle 1 , Fernandes-Rosa Fabio 1 , Hulot Jean-Sebastien 1,2 , Faedda Nicolo 1 , Fayad May 1 , Magnus Chris 3 , Sternson Scott 3 , Travers-Allard Simon 1,4 , Baron Stephanie 4 , Zennaro Maria-Christina 1,5 & Sheerazed Boulkroun 1
1PARCC, INSERM, Université Paris Cité, Paris, France; 2CIC1418 and DMU CARTE, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France; 3Howard Hmghes Medical Institute & Department of Neurosciences, University of California, San Diego, United States; 4Service de Physiologie, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France; 5Service de Génétique, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France
Primary aldosteronism (PA) is the most frequent form of secondary hypertension and is due to autonomous aldosterone production by the adrenal gland. During the last decades, major advances have been made in our understanding of the disease with the identification of germline or somatic mutations in ion channels and pumps. These mutations enhance calcium signaling, the main trigger of aldosterone biosynthesis. The objective of our work was to elucidate, using chemogenetic tools, the molecular mechanisms underlying the development of PA by modulating sodium entry into the cells “on demand” leading to calcium signaling activation. We have developed an adrenocortical H295R-S2 cell line stably expressing a chimeric ion channel receptor formed by the extracellular ligand-binding domain of the a7 nicotinic acetylcholine receptor fused to the ion pore domain of the serotonin receptor 5HT3a named α7-5HT3. Its activation by a selective agonist, the PSEM-817, leads to sodium entry into the cells and activation of calcium signaling. In parallel, we have developed a mouse model expressing the α7-5HT3 receptor specifically in the adrenal cortex. The cells expressing the α7-5HT3 receptor recapitulated the major features of KCNJ5 mutations, the most frequent genetic alteration identified in Aldosterone-Producing-Adenoma. Stimulation of the α7-5HT3 receptor by PSEM-817 resulted in a significant increase in intracellular calcium concentrations, CYP11B2 mRNA expression, and aldosterone biosynthesis and was associated with a decrease in cell proliferation. RNA sequencing and steroidome analyses revealed unique profiles associated with sodium entry. Exploration of adult mice expressing the α7-5HT3 receptor specifically in the adrenal cortex, generated in our laboratory, is ongoing. Preliminary results revealed a significant increase in plasma aldosterone and 18-hydroxycorticosterone levels in male and female mice expressing the a7-5HT3 receptor after four weeks of treatment with PSEM-817 but no major adrenal abnormalities. Our results smggest that increased sodium influx leading to increased calcium signaling is not sufficient to promote both increased aldosterone production and cell proliferation, thus strongly supporting the requirement of additional mechanisms for the development of APA. Altogether, this work offers valuable insights into the role of sodium-induced calcium signalling in PA development and paves the way for developing new therapeutic strategies.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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