Ca2+entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance
Year: 2015
Type: article
Abstract: Ubiquitously expressed Trpm2 channel limits oxidative stress and preserves mitochondrial function. We first demonstrated that intracellular Ca(2+) concentration increase after Trpm2 activation was due to direct Ca(2+) influx and not indirectly via reverse Na(+)/Ca(2+) exchange. To elucidate whether Ca(2+) entry via Trpm2 is required to maintain cellular bioenergetics, we injected adenovirus expressing green fluorescent protein (GFP), wild-type (WT) Trpm2, and loss-of-function (E960D) Trpm2 mutant into left ventricles of global Trpm2 knockout (gKO) or WT hearts. Five days post-injection, gKO-GFP heart slices had higher reactive oxygen species (ROS) levels but lower oxygen consumption rate (OCR) than WT-GFP heart slices. Trpm2 but not E960D decreased ROS and restored OCR in gKO hearts back to normal levels. In gKO myocytes expressing Trpm2 or its mutants, Trpm2 but not E960D reduced the elevated mitochondrial superoxide (O2(.-)) levels in gKO myocytes. After hypoxia-reoxygenation (H/R), Trpm2 but not E906D or P1018L (inactivates Trpm2 current) lowered O2(.-) levels in gKO myocytes and only in the presence of extracellular Ca(2+), indicating sustained Ca(2+) entry is necessary for Trpm2-mediated preservation of mitochondrial function. After ischemic-reperfusion (I/R), cardiac-specific Trpm2 KO hearts exhibited lower maximal first time derivative of LV pressure rise (+dP/dt) than WT hearts in vivo. After doxorubicin treatment, Trpm2 KO mice had worse survival and lower +dP/dt. We conclude 1) cardiac Trpm2-mediated Ca(2+) influx is necessary to maintain mitochondrial function and protect against H/R injury; 2) Ca(2+) influx via cardiac Trpm2 confers protection against H/R and I/R injury by reducing mitochondrial oxidants; and 3) Trpm2 confers protection in doxorubicin cardiomyopathy.
Institutions: Temple University, Pennsylvania State University
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G1069587043, G1175070004, Mechanisms of mitochondrial calcium exchange in heart failure, Novel Mechanisms of Cardiac Injury and Repair, G2911276421, Targeting GRK2 in the Heart, G3270310648, G3459070268, G351814948, Phospholemman and Cardiac Contracility, Involvement of BAG3 in HIV-1 induced cardiomyopathy, G4454727091, Exercise training in post-infarct heart, G490114207, Gene Transfer and Myocardial Function, G5524035666, Coordination of Pathophysiologic endothelial cell signaling by ROS, G7514306230, Signal Transduction Mechanisms of Erythropoietin, GRK and b-Arrestin Signaling in Cardiac Regeneration, Novel Mechanisms and Therapies in Heart Failure
OpenAlex ID: W2023465160