2009
DOI: 10.1253/circj.cj-09-0284
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GSK-3.BETA., a Therapeutic Target for Cardiomyocyte Protection

Abstract: lycogen synthase kinase-3β (GSK-3β) is a constitutively active 47-kDa Ser/Thr protein kinase that was purified more than 2 decades ago as a kinase that reduces glycogen synthase activity. However, GSK-3β is now known as a multifunctional kinase having more than 40 substrates, playing roles not only in glycogen metabolism but also cell proliferation, growth and death. [1][2][3] To properly execute its functions, GSK-3β has multiple regulatory mechanisms including phosphorylation at Ser and Tyr residues, complex… Show more

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Cited by 130 publications
(121 citation statements)
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“…GSK-3b inhibition), which protects the adult-rat heart from I/R injury for 2-4 h. 4,[13][14][15][16] This study showed a link between the Zn 2 þ i release/increase and the activation of GSK-3b, resulting in myocyte apoptosis. We observed an early increase in p-Ser9 GSK-3b levels after Zn 2 þ Figure S2b), we conclude that Zn 2 þ i supplementation-induced early phosphorylation at Ser9 is not necessarily cardioprotective and may induce cytotoxicity after return to normal medium for 4 or 24 h. In support of the above conclusions, Tyr216 phosphorylation is required for nuclear GSK-3b accumulation in neurons and fibroblasts, 17,18 as mutation of Tyr216 to phenylalanine or its dephosphorylation results in less GSK-3b being found in nuclei.…”
Section: Discussionmentioning
confidence: 71%
See 1 more Smart Citation
“…GSK-3b inhibition), which protects the adult-rat heart from I/R injury for 2-4 h. 4,[13][14][15][16] This study showed a link between the Zn 2 þ i release/increase and the activation of GSK-3b, resulting in myocyte apoptosis. We observed an early increase in p-Ser9 GSK-3b levels after Zn 2 þ Figure S2b), we conclude that Zn 2 þ i supplementation-induced early phosphorylation at Ser9 is not necessarily cardioprotective and may induce cytotoxicity after return to normal medium for 4 or 24 h. In support of the above conclusions, Tyr216 phosphorylation is required for nuclear GSK-3b accumulation in neurons and fibroblasts, 17,18 as mutation of Tyr216 to phenylalanine or its dephosphorylation results in less GSK-3b being found in nuclei.…”
Section: Discussionmentioning
confidence: 71%
“…When the reperfusion injury salvage kinase (RISK) family members PKA, PKB/Akt, PKC, and MEK-ERK are activated by pre-or post-conditioning, a common downstream protein, GSK-3b, is phosphorylated at Ser9, resulting in GSK-3b inhibition (both events occurring within 20 min of the end of conditioning), leading to the inhibition of mPTPs and the salvaging of 20-50% live myocardium. 4,5,[13][14][15][16] A potent GSK-3 inhibitor, SB216763 (SB21), 4,13 had a relatively weak protective effect against H 2 O 2 -, ONOO À -induced myocyte death (Supplementary Figure S2c), but gave better protection against 10 mM Zn 2 þ -induced cell toxicity at 4 h (Figure 2d (TUNEL test) were performed as follows: after ischemia for 40 min, followed by reperfusion for 4 h, myocytes were returned to normal medium without inhibitors for 24 h, then were examined for apoptotic markers. Compared with I/R alone ('I/R', Figure 4b), the presence of 15 mM TPEN at the start of reperfusion for only B20 min ('TPEN (20 min)') markedly inhibited I/R injury at 24 h after TPEN removal, suggesting that the reperfusion-induced initial Zn 2 þ i release (Figure 3b) is important in I/R injury.…”
Section: Resultsmentioning
confidence: 99%
“…2a). Inactivation of GSK-3b through phosphorylation at Ser9 (pGSK-3b) is cytoprotective in the myocardium 25,26 and is a common readout of ILK activation 27,28 . ILK overexpression caused an increase in phosphorylation of GSK-3b, whereas ILK knockdown by short interfering RNA (siRNA) caused a relative de-phosphorylation of GSK-3b (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…For example, deletion of OGT led to reduced OGlcNAcylation of VDAC, sensitizing cells to mitochondrial membrane potential collapse and mPTP formation Jones et al 2008). Notably, formation of the mPTP is also promoted by active GSK3β (Juhaszova et al 2004;Miura and Miki 2009), which is inhibited in some models by stress-induced O-GlcNAcylation (Kazemi et al 2010;Ku et al 2010).…”
Section: Mitochondrial Dynamicsmentioning
confidence: 99%