Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death

J Neurochem. 2001 Apr;77(1):94-102. doi: 10.1046/j.1471-4159.2001.t01-1-00251.x.

Abstract

The phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB; also known as Akt) signalling pathway is recognized as playing a central role in the survival of diverse cell types. Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine protein kinase that is one of several known substrates of PKB. PKB phosphorylates GSK-3 in response to insulin and growth factors, which inhibits GSK-3 activity and leads to the modulation of multiple GSK-3 regulated cellular processes. We show that the novel potent and selective small-molecule inhibitors of GSK-3; SB-415286 and SB-216763, protect both central and peripheral nervous system neurones in culture from death induced by reduced PI 3-kinase pathway activity. The inhibition of neuronal death mediated by these compounds correlated with inhibition of GSK-3 activity and modulation of GSK-3 substrates tau and beta-catenin. Thus, in addition to the previously assigned roles of GSK-3, our data provide clear pharmacological and biochemical evidence that selective inhibition of the endogenous pool of GSK-3 activity in primary neurones is sufficient to prevent death, implicating GSK-3 as a physiologically relevant principal regulatory target of the PI 3-kinase/PKB neuronal survival pathway.

MeSH terms

  • Aminophenols / pharmacology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chromones / pharmacology
  • Cytoskeletal Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Indoles / pharmacology
  • Maleimides / pharmacology
  • Morpholines / pharmacology
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt
  • Substrate Specificity
  • Trans-Activators*
  • beta Catenin
  • tau Proteins / metabolism

Substances

  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • CTNNB1 protein, human
  • Chromones
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • Morpholines
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • SB 216763
  • Trans-Activators
  • beta Catenin
  • tau Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Glycogen Synthase Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3