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Ca²⁺-Regulated Expression of Aldosterone Synthase Is Mediated By Calmodulin and Calmodulin-Dependent Protein Kinases

Department of Obstetrics and Gynecology (C.D.C., J.M.M., W.E.R.), University of Texas Southwestern Medical Center, Dallas, Texas 75235-9032; Health Center, Department of Cell Biology (V.P., S.A.), Faculty of Pharmacy, University of Calabria, Rende (CS) 87036, Italy

The chronic maintenance of aldosterone production in the adrenal zona glomerulosa is associated with increased expression of aldosterone synthase (P450aldo), the enzyme responsible for the conversion of 11-deoxycorticosterone to aldosterone. The major physiologic regulators of aldosterone production are angiotensin II (ANG II) and (K⁺) which act in part through increasing intracellular calcium ([Ca²⁺]_i). Recently we demonstrated that increased [Ca²⁺]_i is associated with K⁺ induction of P450aldo expression. To determine whether Ca²⁺ regulation of P450aldo is mediated through calmodulin or calmodulin-dependent kinases (CaMK), we investigated the actions of calmidazolium (a calmodulin inhibitor) and KN93 (an inhibitor of CaMK) on expression of P450aldo in human adrenocortical H295R cell line. Treatment with either calmidazolium or KN93 completely inhibited K⁺-stimulated expression of P450aldo mRNA with little effect on ANG II or dibutyryl cyclic AMP-stimulated induction of this transcript. Cellular calcium levels were also increased using the calcium ionophore ionomycin and calcium channel agonist Bay K 8644. These compounds increased P450aldo mRNA and this calcium induction was inhibited by calmidazolium and KN93. These data show that K⁺-stimulated expression of P450aldo mRNA is regulated in a Ca²⁺ sensitive manner through mechanisms involving calmodulin and CaMK.

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