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. 2020 Oct 1;161(10):bqaa135.
doi: 10.1210/endocr/bqaa135.

Cellular Pathophysiology of Mutant Voltage-Dependent Ca2+ Channel CACNA1H in Primary Aldosteronism

Florian Gürtler  1 , Katrin Jordan  1 , Ines Tegtmeier  1 , Janina Herold  1 , Julia Stindl  1 , Richard Warth  1 , Sascha Bandulik  1
Affiliations

Cellular Pathophysiology of Mutant Voltage-Dependent Ca2+ Channel CACNA1H in Primary Aldosteronism

Florian Gürtler et al. Endocrinology. .

Abstract

The physiological stimulation of aldosterone production in adrenocortical glomerulosa cells by angiotensin II and high plasma K+ depends on the depolarization of the cell membrane potential and the subsequent Ca2+ influx via voltage-activated Ca2+ channels. Germline mutations of the low-voltage activated T-type Ca2+ channel CACNA1H (Cav3.2) have been found in patients with primary aldosteronism. Here, we investigated the electrophysiology and Ca2+ signaling of adrenal NCI-H295R cells overexpressing CACNA1H wildtype and mutant M1549V in order to understand how mutant CACNA1H alters adrenal cell function. Whole-cell patch-clamp measurements revealed a strong activation of mutant CACNA1H at the resting membrane potential of adrenal cells. Both the expression of wildtype and mutant CACNA1H led to a depolarized membrane potential. In addition, cells expressing mutant CACNA1H developed pronounced action potential-like membrane voltage oscillations. Ca2+ measurements showed an increased basal Ca2+ activity, an altered K+ sensitivity, and abnormal oscillating Ca2+ changes in cells with mutant CACNA1H. In addition, removal of extracellular Na+ reduced CACNA1H current, voltage oscillations, and Ca2+ levels in mutant cells, suggesting a role of the partial Na+ conductance of CACNA1H in cellular pathology. In conclusion, the pathogenesis of stimulus-independent aldosterone production in patients with CACNA1H mutations involves several factors: i) a loss of normal control of the membrane potential, ii) an increased Ca2+ influx at basal conditions, and iii) alterations in sensitivity to extracellular K+ and Na+. Finally, our findings underline the importance of CACNA1H in the control of aldosterone production and support the concept of the glomerulosa cell as an electrical oscillator.

Keywords: CaV3.2; adrenal gland; membrane voltage oscillation; primary aldosteronism; voltage-activated T-type calcium channel.

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