Targeting GSK-3 family members in the heart: a very sharp double-edged sword

J Mol Cell Cardiol. 2011 Oct;51(4):607-13. doi: 10.1016/j.yjmcc.2010.11.020. Epub 2010 Dec 13.

Abstract

The GSK-3 family of serine/threonine kinases, which is comprised of two isoforms (α and β), was initially identified as a negative regulator of glycogen synthase, the rate limiting enzyme of glycogen synthesis [1,2]. In the 30 years since its initial discovery, the family has been reported to regulate a host of additional cellular processes and, consequently, disease states such as bipolar disorders, diabetes, inflammatory diseases, cancer, and neurodegenerative diseases including Alzheimer's Disease and Parkinson's Disease [3,4]. As a result, there has been intense interest on the part of the pharmaceutical industry in developing small molecule antagonists of GSK-3. Herein, we will review the roles played by GSK-3s in the heart, focusing primarily on recent studies that have employed global and tissue-specific gene deletion. We will highlight roles in various pathologic processes, including pressure overload and ischemic injury, focusing on some striking isoform-specific effects of the family. Due to space limitations and/or the relatively limited data in gene-targeted mice, we will not be addressing the family's roles in ischemic pre-conditioning or its many interactions with various pro- and anti-apoptotic factors. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

Publication types

  • Review

MeSH terms

  • Animals
  • Cardiomegaly / drug therapy
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cell Differentiation
  • Cell Proliferation
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / metabolism
  • Embryonic Stem Cells / physiology
  • Gene Deletion
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Insulin Resistance
  • Molecular Targeted Therapy*
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Translational Medical Research
  • Ventricular Remodeling / drug effects

Substances

  • Protein Kinase Inhibitors
  • Glycogen Synthase Kinase 3