[Frontiers in Bioscience 14, 1558-1570, January 1, 2009]
GSK-3 inhibitors and insulin receptor signaling in health, disease, and therapeutics
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan
TABLE OF CONTENTS
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-3a (51 kDa)/-3b (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-3b/b-catenin signaling pathway by therapeutic drugs (5) are useful. Chemical structures of GSK-3 inhibitors are listed in the review articles (2, 4).