DEVELOPMENT OF AN ADRENOCORTICAL CELL MODEL OF CALCIUM SIGNALING MODULATION TO DECIPHER THE MOLECULAR MECHANISMS RESPONSIBLE FOR PRIMARY ALDOSTERONISM

醛固酮 生物学中的钙 细胞生物学 内分泌学 钙信号传导 内科学 受体 细胞内 生物 医学
作者
Bakhta Fedlaoui,Teresa Cosentino,Zeina R. Al Sayed,Isabelle Giscos-Douriez,Fábio L. Fernandes‐Rosa,Jean‐Sébastien Hulot,Chris Magnus,Scott M. Sternson,Maria‐Christina Zennaro,Sheerazed Boulkroun
出处
期刊:Journal of Hypertension [Lippincott Williams & Wilkins]
卷期号:40 (Suppl 1): e32-e33
标识
DOI:10.1097/01.hjh.0000835560.60928.a2
摘要

Primary aldosteronism (PA) is the most frequent form of secondary hypertension. The identification of germline or somatic mutations in different genes coding for ion channels (KCNJ5, CACNA1D, CACNA1H and CLCN2) and ATPases (ATP1A1 and ATP2B3) defines PA as a channelopathy. These mutations promote activation of calcium signaling, the main trigger for 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, mimicking some of known mutations identified in PA.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 α7 nicotinic acetylcholine receptor fused to the ion pore domain of the serotonin receptor 5HT3α and named α7-5HT3. Mutations have been introduced in the ligand binding domain to allow only synthetic drugs to activate this channel receptor. Activation of α7-5HT3 by a specific drug, PSEM-817 leads to sodium entry into the cells. This cell line was characterized in terms of intracellular calcium concentrations, cell proliferation, aldosterone production, steroidogenic expression and electrophysiological properties.Treatment of α7-5HT3 expressing cells with increasing concentration of PSEM-817 (from 10-9 to 10-5 M) induced a significant increase in intracellular calcium concentrations, similarly to potassium (12 mM) or angiotensin II (10-8 M). This stimulation of calcium signaling did not affect cell proliferation, but was responsible for an increase in CYP11B2 expression and aldosterone production after 24 h of treatment. However, while increased intracellular calcium concentrations were observed starting from 10-8 M of PSEM-817, CYP11B2 expression and aldosterone production were only affected starting from 10-7 M, suggesting a dose dependent effect. Finally, whereas cells were hyperpolarized in absence of stimulation (around -60 mV), PSEM-817 induced a strong depolarization, cells rising to a membrane potential around -10 mV.This cell line, in which we can modulate the intracellular calcium concentration "on demand", is a useful tool for a better understanding of the alterations of intracellular ion balance and calcium signaling in the pathophysiology of PA.
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