[Frontiers in Bioscience 14, 1558-1570, January 1, 2009]

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

Akihiko Wada

Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan


1. Abstract
2. Introduction
3. New aspects of lithium and glycogen synthase kinase-3b (GSK-3b) in psychiatric diseases
4. Preclinical efficiency of GSK-3 inhibitors
4.1. Diabetes mellitus
4.2. Inflammation
4.3. Neurodegenerative diseases
4.3.1. Alzheimer's disease
4.3.2. Parkinson's disease
4.3.3. Amyotrophic lateral sclerosis
4.3.4. Huntington's disease
4.4. Cell protection against various stresses
4.5. Self-renewal and pluripotency of embryonic stem cells
4.6. Neurogenesis and neuronal differentiation
5. Ser21/Ser9-phosphorylation of GSK-3a/b by various classical therapeutic drugs
6. Neuronal insulin receptor signaling and GSK-3
7. Insulin receptor signaling in adrenal chromaffin cells
7.1. Insulin/insulin-like growth factor-I (IGF-I)/GSK-3b pathway: up-regulation of voltage-dependent Nav1.7 .sodium channel
7.2. Reduction of insulin receptor, insulin receptor substrate-1 (IRS-1), IRS-2 and Akt1 levels by GSK-3b inhibitors
7.3. Insulin receptor expression by 90-kDa heat-shock protein, endoplasmic reticulum Ca2+-ATPase, peptidyl prolyl cis-trans isomerase activity of cytoplasmic immunophilins, protein kinase C-a, and acetoacetate
7.4. Up-regulation of IRS-1 and IRS-2 by nicotinic receptor/protein kinase C-a/extracellular signal-regulated kinase (ERK) pathway
7.5. Proteasomal degradation of IRS-2 by calcineurin inhibition
8. Acknowledgments
9. References


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).