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Aldosterone Increases T-Type Calcium Currents in Human Adrenocarcinoma (H295R) Cells by Inducing Channel Expression

Division of Endocrinology and Diabetology, (O.L., M.F.R.) Department of Internal Medicine, Laboratory of Clinical Chemistry (A.C., M.F.R.), Department of Pathology, University Hospital, Geneva 14, Switzerland

Address all correspondence and requests for reprints to: Dr. Michel F. Rossier, Division of Endocrinology and Diabetology, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail: rossier{at}cmu.unige.ch

In adrenal glomerulosa cells, low-threshold voltage-activated (T-type) calcium channels are known to play a crucial role in coupling physiological variations of extracellular potassium to aldosterone biosynthesis. On the other hand, aldosterone itself has been recently shown to regulate Ca²⁺ currents in its target cells. In the present study, we have investigated the effect of aldosterone on Ca²⁺ channels of the steroidogenic human adrenocarcinoma cell line, using both electrophysiological and molecular techniques. Cell incubation with aldosterone (1 µM) for 24 h increased by 39% the density of T-type calcium currents, as assessed with the patch clamp technique. This effect of aldosterone was not related to a modification of T channel activation and inactivation properties. In contrast, L-type calcium currents remained unaffected by aldosterone treatment. The mineralocorticoid receptor antagonist, spironolactone, blunted the aldosterone-induced increase in T-type calcium current. By RT-PCR, we detected in human adrenocarcinoma cells the presence of mRNA coding for the ₁ subunits of three different calcium channels: the ₁H isoform of T channels and the ₁C and ₁D isoforms of the L channels. The presence of mRNA coding for the mineralocorticoid receptor was also found in these cells. Aldosterone treatment induced a 36% increase of mRNA coding for ₁H, as assessed by real-time PCR. This aldosterone-evoked stimulation of mRNA expression was maximal at 24–48 h and reversed by spironolactone, suggesting a receptor-mediated genomic effect of aldosterone. Pregnenolone production in response to KCl stimulation was increased after aldosterone treatment, in parallel to T channel expression, confirming the essential role of these channels in the steroidogenic response to potassium. Taken together, these data indicate that, in human adrenocarcinoma cells, aldosterone increases, through an autocrine pathway, the expression of T-type calcium channels and therefore modifies the ability of these cells to respond to steroidogenic agonists.

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