A Key Role for TRPM7 Channels in Anoxic Neuronal Death

Maybe #1 in my list of neuronal cascade of death items is not really a problem. Or at least not an easy problem to solve.
1.  Excitotoxicity
2.  Glutamate poisoning
3.  Capillaries that don't open due to pericytes
4.  Inflammatory action leaking through the blood brain barrier
5. Lysosomal Membrane Permeabilization as a Key Player in Brain Ischemic Cell Death.
6.   Reperfusion injury
http://www.cell.com/retrieve/pii/S0092867403010171

Cell, Volume 115, Issue 7, 863-877, 26 December 2003
Copyright © 2003 Cell Press All rights reserved.

Authors

Michelle Aarts, Koji Iihara, Wen-Li Wei, Zhi-Gang Xiong, Mark Arundine, Waldy Cerwinski, John F. MacDonald, Michael TymianskiSee Affiliations

Abstract

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 (I_OGD). I_OGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca²⁺ overload and further ROS production despite AET. I_OGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking I_OGD 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.