Aldosterone signaling through transient receptor potential melastatin 7 cation channel (TRPM7) and its ¦Á-kinase domain

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• 作者：Alvaro Yogi ; Glaucia E. Callera ; Sarah O'Connor ; Tayze T. Antunes ; William Valinsky ; Perrine Miquel ; Augusto C.I. Montezano ; Anne-Laure Perraud ; Carsten Schmitz ; Alvin Shrier ; Rhian M. Touyz
• 关键词：TRPM7 ; Aldosterone ; Signal transduction ; Mg2  ; +
• 刊名：Cellular Signalling
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：25
• 期：11
• 页码：2163-2175
• 全文大小：1541 K

文摘

We demonstrated a role for the Mg^2 + transporter TRPM7, a bifunctional protein with channel and ¦Á-kinase domains, in aldosterone signaling. Molecular mechanisms underlying this are elusive. Here we investigated the function of TRPM7 and its ¦Á-kinase domain on Mg^2 + and pro-inflammatory signaling by aldosterone. Kidney cells (HEK-293) expressing wild-type human TRPM7 (WThTRPM7) or constructs in which the ¦Á-kinase domain was deleted (¦¤Kinase) or rendered inactive with a point mutation in the ATP binding site of the ¦Á-kinase domain (K1648R) were studied. Aldosterone rapidly increased [Mg^2 +]_i and stimulated NADPH oxidase-derived generation of reactive oxygen species (ROS) in WT hTRPM7 and TRPM7 kinase dead mutant cells. Translocation of annexin-1 and calpain-II and spectrin cleavage (calpain target) were increased by aldosterone in WT hTRPM7 cells but not in ¦Á-kinase-deficient cells. Aldosterone stimulated phosphorylation of MAP kinases and increased expression of pro-inflammatory mediators ICAM-1, Cox-2 and PAI-1 in ¦¤kinase and K1648R cells, effects that were inhibited by eplerenone (mineralocorticoid receptor (MR) blocker). 2-APB, a TRPM7 channel inhibitor, abrogated aldosterone-induced Mg^2 + responses in WT hTRPM7 and mutant cells. In 2-APB-treated ¦¤Kinase and K1648R cells, aldosterone-stimulated inflammatory responses were unchanged. These data indicate that aldosterone stimulates Mg^2 + influx and ROS production in a TRPM7-sensitive, kinase-insensitive manner, whereas activation of annexin-1 requires the TRPM7 kinase domain. Moreover TRPM7 ¦Á-kinase modulates inflammatory signaling by aldosterone in a TRPM7 channel/Mg^2 +-independent manner. Our findings identify novel mechanisms for non-genomic actions of aldosterone involving differential signaling through MR-activated TRPM7 channel and ¦Á-kinase.