A Key Role for TRPM7 Channels in Anoxic Neuronal Death

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 (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.

Mitochondrial dynamics in the regulation of neuronal cell death

“…A transient increase of mitochondrial fusion after acute neuronal insult could possibly protect cells from excitotoxicity. Both our group and Barsoum et al have shown that fusion protects against ROS [30,76], which can also lead to Ca 2+ influx through TRMP7 channels [125]. In contrast to neuronal cell death, in HeLa cells mitochondrial fission can protect against death induced by the propagation of Ca 2+ waves along the mitochondria [126].…”

“…Indeed, Opa1 overexpression rescues cell death by maintaining Fig. 3 Activation of the mitochondrial fusion protein Mfn2 or inhibition of the fission protein Drp1 can enhance mitochondrial fusion in cortical neurons, which can protect mitochondria from fragmentation during neuronal cell death induced by oxidative stress (H 2 O 2 ) and subsequently, inhibition of cell death [125]. Cortical neurons from E15.5 mice were infected with the indicated construct via adenoviral vector at the time of plating.…”

The Mg2+ and Mg2+-Nucleotide-Regulated Channel-Kinase TRPM7

“…A further role of TRPM7 in neuronal cells has been suggested by Aarts et al (2003), who subjected cultured cortical neurons to prolonged oxygen and glucose deprivation (OGD), an experimental model for ischemia that causes anoxic cell death. OGD caused significant influx of Ca 2+ that correlated with the amount of cell death.…”

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

“…For instance, two genes essential for sensory physiology, TRPV1 and Drosophila TRPL, were found to be only slightly more permeable to Ca 2+ than to Mg 2+ (Caterina et al 1997;Reuss et al 1997). Finally, two recent reports suggest that TRPM7-mediated Ca 2+ influx is involved in anoxic neuronal cell death and in regulation of the cell cycle of human retinoblastoma cells (Aarts et al 2003;Hanano et al 2004). Thus, additional experiments are required to elucidate whether the biological role of TRPM6 and TRPM7 channels is restricted to Mg 2+ homeostasis.…”