TY - JOUR
T1 - A Key Role for TRPM7 Channels in Anoxic Neuronal Death
AU - Aarts, Michelle
AU - Iihara, Koji
AU - Wei, Wen Li
AU - Xiong, Zhi Gang
AU - Arundine, Mark
AU - Cerwinski, Waldy
AU - MacDonald, John F.
AU - Tymianski, Michael
N1 - Funding Information:
Supported by NIH Grant NS 39060 (M.T.), the Ontario Heart and Stroke Foundation, Canadian Institutes of Health Research (CIHR), and the Canadian Stroke Networks (M.T., J.F.M.). M.A. is a fellow of the Ontario Heart and Stroke Foundation. M.A. is a student and M.T. a Clinician-Scientist of the CIHR. We thank Drs. M.P. Goldberg, M.W. Salter, Y.T. Wang and L. Schlichter for a critical review of the manuscript; Dr. David Nicholls for useful discussions about chemical anoxia; Chang Bai Liu and E. Czerwinska for technical assistance; and Dr. A. Scharenberg for the Flag–murine TRPM7/pCDNA4-TO cDNA.
PY - 2003/12/26
Y1 - 2003/12/26
N2 - Excitotoxicity in brain ischemia triggers neuronal death and neurological disability, and yet these are not prevented by antiexcitotoxic therapy (AET) in humans. Here, we show that in neurons subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a dominant death mechanism perpetuated by a Ca2+-permeable nonselective cation conductance (IOGD). IOGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca2+ overload and further ROS production despite AET. IOGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death. TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia. Thus, excitotoxicity is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role.
AB - Excitotoxicity in brain ischemia triggers neuronal death and neurological disability, and yet these are not prevented by antiexcitotoxic therapy (AET) in humans. Here, we show that in neurons subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a dominant death mechanism perpetuated by a Ca2+-permeable nonselective cation conductance (IOGD). IOGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca2+ overload and further ROS production despite AET. IOGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death. TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia. Thus, excitotoxicity is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role.
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U2 - 10.1016/S0092-8674(03)01017-1
DO - 10.1016/S0092-8674(03)01017-1
M3 - Article
C2 - 14697204
AN - SCOPUS:0346186100
SN - 0092-8674
VL - 115
SP - 863
EP - 877
JO - Cell
JF - Cell
IS - 7
ER -