GSK-3 inhibitors and insulin receptor signaling in health, disease, and therapeutics

Front Biosci (Landmark Ed). 2009 Jan 1;14:1558-70. doi: 10.2741/3324.

Abstract

GSK-3 is constitutively active in nonstimulated cells; multiple signalings negatively regulate GSK-3 via GSK-3 phosphorylation, subcellular (i.e. cytoplasmic; nuclear; mitochondrial) localization, and interaction with other proteins. GSK-3 alpha (51 kDa)/-3 beta (47 kDa) are encoded by different genes. Dysregulated hyperactivity of GSK-3 is associated with various diseases; in vivo and in vitro studies have increasingly implicated that GSK-3 inhibitors are promising therapeutics in diabetes mellitus, inflammation, tumorigenesis, psychiatric/neurodegenerative diseases, ischemia, and stem cell regeneration. Importantly, GSK-3 is the common target for various classical therapeutic drugs. In adrenal chromaffin cells, GSK-3 inhibition caused up-regulation of voltage-dependent Nav1.7 sodium channel, enhancing voltage-dependent calcium channel gating and catecholamine exocytosis; conversely, chronic treatment with GSK-3 inhibitors caused down-regulation of insulin receptor, IRS-1, IRS-2, and Akt1 levels. In this review, I will focus on these recent topics. Comprehensive review articles about lithium (1), GSK-3 and GSK-3 inhibitors (2-4), and the inhibition of Wnt/GSK-3beta>/beta-catenin signaling pathway by therapeutic drugs (5) are useful. Chemical structures of GSK-3 inhibitors are listed in the review articles (2, 4).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Chromaffin Cells / cytology
  • Chromaffin Cells / metabolism
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / chemistry
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Lithium Compounds / pharmacology
  • Lithium Compounds / therapeutic use
  • Mental Disorders / drug therapy
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor, Insulin / metabolism*
  • Serine / metabolism
  • Signal Transduction*

Substances

  • Lithium Compounds
  • Protein Kinase Inhibitors
  • Serine
  • Receptor, Insulin
  • Glycogen Synthase Kinase 3