Guertler, Florian and Jordan, Katrin and Tegtmeier, Ines and Herold, Janina and Stindl, Julia and Warth, Richard and Bandulik, Sascha (2020) Cellular Pathophysiology of Mutant Voltage-Dependent Ca2+ Channel CACNA1H in Primary Aldosteronism. ENDOCRINOLOGY, 161 (10): bqaa135. ISSN 0013-7227, 1945-7170
Full text not available from this repository. (Request a copy)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 Ca(2+ )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 increasedCa(2+) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RAT ADRENAL GLOMERULOSA; ANGIOTENSIN-II; CALCIUM-CHANNELS; K+ CHANNEL; MEMBRANE DEPOLARIZATION; POTASSIUM CHANNELS; CYTOSOLIC CALCIUM; LOW-RENIN; ANG-II; CELLS; adrenal gland; primary aldosteronism; voltage-activated T-type calcium channel; CaV3.2; membrane voltage oscillation |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Richard Warth |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Mar 2021 07:28 |
| Last Modified: | 10 Mar 2021 07:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43652 |
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