Store Operated Calcium Channels, New Targets of Aldosterone in Cardiomyocytes

Recently, the Store-Operated Ca2+ Entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that upregulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidences suggest that the mineralocorticoid hormone, aldosterone, through activation of its receptor (MR), might be a key regulator of Ca2+ influx in cardiomyocytes.We thus assessed whether and how SOCE involving TRPCs (Transient Receptor Potential Canonical) and Orai1 channels are regulated by aldosterone/MR in ventricular cardiomyocytes.Molecular screening using qRT-PCR and western-blot demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, TRPC4, TRPC5 and STIM1 through MR activation. These effects were correlated with a specific enhancement of SOCE sensitive to SOC inhibitors (SKF-96365 and BTP2), to the potent Orai1 blocker, S66 and were prevented by TRPC1, TRPC4 and Orai1 dominant negative-mutants, or TRPC5 siRNA. Mechanistic approach showed that upregulation of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24 h aldosterone-enhanced SOCE is associated with increased diastolic [Ca2+]i which is blunted by SOC inhibitors.Our study provides the first evidence that aldosterone promotes TRPC1, TRPC4, TRPC5 and Orai1-mediated SOCE in cardiomyocytes, through MR and SGK1 pathway.