Does inhibition of glycogen synthase kinase protect

Preconditioning (PreC) and postconditioning (PostC) have been shown to initiate a number of signaling cascades that reduce cell death. However the mechanisms by which these signals reduce cell death have been elusive (1). PreC has been shown to phosphorylate and thereby inhibit GSK-3β, and perfusion with GSK inhibitors have been shown to reduce cell death induced by ischemia-reperfusion, when added before ischemia (2) or when added at the start of reperfusion (3,4,5). These studies are consistent with data in other tissues showing that inhibition of GSK-3β reduces apoptosis. Information regarding the mechanism by which inhibition of GSK protects was provided by Juhaszova et al (6) who reported that inhibition of GSK-3β delays the opening of the mitochondrial permeability transition pore (MPT) (see figure). The MPT is a large conductance pore in the inner mitochondrial membrane which is opened under conditions associated with ischemia-reperfusion such as high matrix reactive oxygen species and high matrix calcium. Pharmacological inhibitors of the MPT have been shown to reduce ischemia-reperfusion injury, suggesting that activation of MPT might have a role in ischemia-reperfusion mediated cell death. However the molecular components of the MPT have not been identified (7)