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Aldosterone signaling through transient receptor potential melastatin 7 cation channel (TRPM7) and its α-kinase domain
We demonstrated a role for the Mg2+ transporter TRPM7, a bifunctional protein with channel and α-kinase domains, in aldosterone signaling. Molecular mechanisms underlying this are elusive. Here we investigated the function of TRPM7 and its α-kinase domain on Mg2+ and pro-inflammatory signaling by al...
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Published in: | Cellular signalling 2013-11, Vol.25 (11), p.2163-2175 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | We demonstrated a role for the Mg2+ transporter TRPM7, a bifunctional protein with channel and α-kinase domains, in aldosterone signaling. Molecular mechanisms underlying this are elusive. Here we investigated the function of TRPM7 and its α-kinase domain on Mg2+ and pro-inflammatory signaling by aldosterone. Kidney cells (HEK-293) expressing wild-type human TRPM7 (WThTRPM7) or constructs in which the α-kinase domain was deleted (ΔKinase) or rendered inactive with a point mutation in the ATP binding site of the α-kinase domain (K1648R) were studied. Aldosterone rapidly increased [Mg2+]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 α-kinase-deficient cells. Aldosterone stimulated phosphorylation of MAP kinases and increased expression of pro-inflammatory mediators ICAM-1, Cox-2 and PAI-1 in Δkinase and K1648R cells, effects that were inhibited by eplerenone (mineralocorticoid receptor (MR) blocker). 2-APB, a TRPM7 channel inhibitor, abrogated aldosterone-induced Mg2+ responses in WT hTRPM7 and mutant cells. In 2-APB-treated ΔKinase and K1648R cells, aldosterone-stimulated inflammatory responses were unchanged. These data indicate that aldosterone stimulates Mg2+ influx and ROS production in a TRPM7-sensitive, kinase-insensitive manner, whereas activation of annexin-1 requires the TRPM7 kinase domain. Moreover TRPM7 α-kinase modulates inflammatory signaling by aldosterone in a TRPM7 channel/Mg2+-independent manner. Our findings identify novel mechanisms for non-genomic actions of aldosterone involving differential signaling through MR-activated TRPM7 channel and α-kinase.
•TRPM7 plays an important role in non-genomic signalling of aldosterone.•TRPM7 and its α-kinase domain have differential functions in aldosterone signaling.•Aldosterone mediates Mg2+ influx and ROS generation via TRPM7 channel.•Inflammatory signaling induced by aldosterone involves TRPM7 α -kinase domain.•Pleiotropic actions of aldosterone may involve TRPM7 channel or its kinase domain. |
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ISSN: | 0898-6568 1873-3913 |
DOI: | 10.1016/j.cellsig.2013.07.002 |