title: Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels: NEW TARGETS OF ALDOSTERONE IN CARDIOMYOCYTES.
abstract: Store-operated Ca(2+) entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that up-regulate 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 evidence suggests that the mineralocorticoid hormone aldosterone, through activation of its receptor, MR, might be a key regulator of Ca(2+) influx in cardiomyocytes. We thus assessed whether and how SOCE involving transient receptor potential canonical (TRPC) and Orai1 channels are regulated by aldosterone/MR in neonatal rat ventricular cardiomyocytes. Molecular screening using qRT-PCR and Western blotting demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, -C4, -C5, and stromal interaction molecule 1 through MR activation. These effects were correlated with a specific enhancement of SOCE activities sensitive to store-operated channel inhibitors (SKF-96365 and BTP2) and to a potent Orai1 blocker (S66) and were prevented by TRPC1, -C4, and Orai1 dominant negative mutants or TRPC5 siRNA. A mechanistic approach showed that up-regulation of serum- and glucocorticoid-regulated kinase 1 mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24-h aldosterone-enhanced SOCE is associated with increased diastolic [Ca(2+)]i, which is blunted by store-operated channel inhibitors. Our study provides the first evidence that aldosterone promotes TRPC1-, -C4-, -C5-, and Orai1-mediated SOCE in cardiomyocytes through an MR and serum- and glucocorticoid-regulated kinase 1 pathway.
authors.affiliation: From the UMR S1180, INSERM, Université Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France and jessica.sabourin@u-psud.fr.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sabourin
authors.affiliation: From the UMR S1180, INSERM, Université Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France and.
authors.forename: Fiona
authors.initials: F
authors.lastname: Bartoli
authors.affiliation: UMR S999, INSERM, Université Paris-Sud, Université Paris-Saclay, Centre Chirurgical Marie Lannelongue, 92350 Le Plessis Robinson, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Antigny
authors.affiliation: From the UMR S1180, INSERM, Université Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France and.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gomez
authors.affiliation: From the UMR S1180, INSERM, Université Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France and.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benitah
mesh_terms: D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling; D002478:Cells, Cultured; D015870:Gene Expression; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000071740:ORAI1 Protein; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017208:Rats, Wistar; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D000813:Anilides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007093:Imidazoles; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; D017346:Protein Serine-Threonine Kinases; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; D013830:Thiadiazoles; D000099184:Serum-Glucocorticoid Regulated Kinases; C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; C532493:Orai1 protein, rat; C518857:Stim1 protein, rat; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
keywords: aldosterone; calcium channel; calcium imaging; calcium release-activated calcium channel protein 1 (ORAI1); cardiomyocyte