“…The importance of our results resides in the fact that, at the concentrations of Mg 2ϩ and ATP present in the cytoplasm, only high activity channels, such as those that preferentially emerged during ischemia, are sufficiently activated by Ca 2ϩ to sustain CICR (Bull et al, 2007). Previous experiments, showing that RyR inhibition with dantrolene reduces the sustained [Ca 2ϩ ] increase and the subsequent neuronal death in animal models of ischemia, support the hypothesis that RyR channels mediate CICR during ischemia (Frandsen and Schousboe, 1991;Zhang et al, 1993;Wei and Perry, 1996;Yano et al, 2001;Clodfelter et al, 2002;Nakayama et al, 2002;Li et al, 2005). We propose that local production of reactive species caused by ischemia initially increases markedly the high activity response of RyR channels by S-glutathionylation of RyR2 and thus facilitates RyR-mediated CICR in brain cortex and steadily amplifies the cytoplasmic [Ca 2ϩ ] increase produced by ischemia-enhanced Ca 2ϩ entry.…”