title: A key role for Mg(2+) in TRPM7's control of ROS levels during cell stress.
abstract: The TRPM7 (transient receptor potential melastatin 7) channel has been shown to play a pivotal role in cell survival during brain ischaemia as well as in the survival of other cell types challenged with apoptotic stimuli. Ca(2+) is thought to be central to the channel's ability to regulate ROS (reactive oxygen species) production. However, channel-mediated entry of Mg(2+) and Zn(2+) have also been implicated in cell death. In the present study, we show that depletion of TRPM7 by RNA interference in fibroblasts increases cell resistance to apoptotic stimuli by decreasing ROS levels in an Mg(2+)-dependent manner. Depletion of TRPM7 lowered cellular Mg(2+), decreased the concentration of ROS and lessened p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) activation as well as decreased caspase 3 activation and PARP [poly(ADP-ribose) polymerase] cleavage in response to apoptotic stimuli. Re-expression of TRPM7 or of a kinase-inactive mutant of TRPM7 in TRPM7-knockdown cells increased cellular Mg(2+) and ROS levels, as did expression of the Mg(2+) transporter SLC41A2 (solute carrier family 41 member 2). In addition, expression of SLC41A2 increased the sensitivity of TRPM7-knockdown cells to apoptotic stimuli and boosted ROS generation in response to cell stress. Taken together, these data uncover an essential role for Mg(2+) in TRPM7's control of cell survival and in the regulation of cellular ROS levels.
authors.affiliation: Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Hsiang-Chin
authors.initials: HC
authors.lastname: Chen
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Su
authors.forename: Omayra
authors.initials: O
authors.lastname: González-Pagán
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Overton
authors.forename: Loren W
authors.initials: LW
authors.lastname: Runnels
mesh_terms: D000818:Animals; D017209:Apoptosis; D027682:Cation Transport Proteins / Q000378:metabolism; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D041701:Swiss 3T3 Cells; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C501065:Slc41a2 protein, mouse; D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008274:Magnesium