GSK-3 inhibitors and insulin receptor signaling in health, disease, and therapeutics.
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).
Wada
Akihiko
A
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan. akihiko@fc.miyazakiu.ac.jp
D019439:Chromaffin Cells / Q000166:cytology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001523:Mental Disorders / Q000188:drug therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011972:Receptor, Insulin / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
D018020:Lithium Compounds; D047428:Protein Kinase Inhibitors; D012694:Serine; D011972:Receptor, Insulin; D038362:Glycogen Synthase Kinase 3