Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional Ser/Thr
kinase that plays important roles in
necrosis and apoptosis of cardiomyocytes. A major mechanism of cell
necrosis is the opening of the
mitochondrial permeability transition pore (mPTP), which consists of multiple
protein subunits, including
adenine nucleotide translocase (ANT). The threshold for
mPTP opening is elevated by phosphorylation of
GSK-3beta at Ser9, which reduces activity of this
kinase. How inactivation of
GSK-3beta suppresses
mPTP opening has not been fully understood, but evidence to date suggests that preservation of
hexokinase-II in the
mPTP complex, inhibition of
cyclophilin-D-ANT binding, inhibition of p53 and inhibition of ANT into the mitochondria are contributory.
GSK-3beta phosphorylation is a step to which multiple protective signaling pathways converge, and thus
GSK-3beta phosphorylation is crucial in cardioprotection of a variety of interventions against
ischemia/reperfusion injury. Apoptosis of cardiomyocytes by pressure overload or
ischemia/reperfusion is also suppressed by inactivation of
GSK-3beta, in which reduced phosphorylation of p53, heat shock factor-1 and myeloid cell
leukemia sequence-1 and inhibition of Bax translocation might be involved. Considering predominant roles of
GSK-3beta in cardiomyocyte death, manipulation of this
protein kinase is a promising strategy for myocardial protection in
coronary artery disease and
heart failure.