TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia

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Ye, M ; Yang, W ; Ainscough, JF ; Hu, X-P ; Li, X ; Sedo, A ; Zhang, X-H ; Zhang, X ; Chen, Z ; Li, X-M ; Beech, DJ ; Sivaprasadarao, A ; Luo, J-H ; Jiang, L-H (2014)
  • Publisher: Nature Publishing Group
  • Subject:
    mesheuropmc: parasitic diseases
    acm: TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY

Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn<sup>2+</sup> level ([Zn<sup>2+</sup>]<inf>c</inf>) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia-reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn<sup>2+</sup>]<inf>c</inf>, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn<sup>2+</sup>]<inf>c</inf> but abolished the cytosolic Zn<sup>2+</sup> accumulation during reperfusion as well as ROS-elicited increases in the [Zn<sup>2+</sup>]<inf>c</inf>. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn<sup>2+</sup>]<inf>c</inf> and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury.
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