title: Aldosterone Upregulates Transient Receptor Potential Melastatin 7 (TRPM7).
abstract: Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed Mg(2+)-permeable ion channel fused to a C-terminal α-kinase domain. Recently, aldosterone was shown to increase intracellular Mg(2+) levels and alter inflammatory signaling in TRPM7-expressing HEK293 cells. This study was undertaken to assess whether these effects were related to an aldosterone-mediated increase of TRPM7 current and/or plasma membrane localization. Using HEK293 cells stably expressing WT-TRPM7, we found that 18-h application of aldosterone significantly increased TRPM7 current and TRPM7 plasma membrane protein expression by 48% and 34%, respectively. The aldosterone-mediated increase of TRPM7 current was inhibited by eplerenone, a mineralocorticoid receptor (MR) blocker, and GSK-650394, an inhibitor of the serum- and glucocorticoid-regulated kinase 1 (SGK1). SGK1 blockade also prevented the aldosterone-induced increase of TRPM7 plasma membrane protein. It was further determined that K1648R-TRPM7, the phosphotransferase-inactive TRPM7 mutant, was unresponsive to aldosterone. Therefore, chronic aldosterone treatment increases the plasma membrane expression of TRPM7, which is associated with an increase of TRPM7 current. This process occurs via an MR-dependent, genomic signaling cascade involving SGK1 and a functioning TRPM7 α-kinase domain. We suggest that this mechanism may be of general relevance when interpreting the effects of aldosterone because the MR receptor is found in multiple tissues, and TRPM7 and SGK1 are ubiquitously expressed.
authors.affiliation: From the Department of Physiology, McGill University, Montreal, Quebec H3G 0B1, Canada and.
authors.forename: William C
authors.initials: WC
authors.lastname: Valinsky
authors.affiliation: From the Department of Physiology, McGill University, Montreal, Quebec H3G 0B1, Canada and.
authors.forename: Anna
authors.initials: A
authors.lastname: Jolly
authors.affiliation: From the Department of Physiology, McGill University, Montreal, Quebec H3G 0B1, Canada and.
authors.forename: Perrine
authors.initials: P
authors.lastname: Miquel
authors.affiliation: the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF GCRC, 126 University Place, Glasgow G12 8TA, United Kingdom.
authors.forename: Rhian M
authors.identifier: 0000-0003-0670-0887
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: From the Department of Physiology, McGill University, Montreal, Quebec H3G 0B1, Canada and alvin.shrier@mcgill.ca.
authors.forename: Alvin
authors.identifier: 0000-0002-6133-4931
authors.initials: A
authors.lastname: Shrier
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D000077545:Eplerenone; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000077545:Eplerenone; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D050053:TRPM Cation Channels; D000099184:Serum-Glucocorticoid Regulated Kinases; C532254:2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid; C486583:TRPM7 protein, human
keywords: SGK1; aldosterone; electrophysiology; mineralocorticoid receptor; plasma membrane; transient receptor potential channels (TRP channels); α-kinase