title: [AMP-activated protein kinase: how a mistake in energy gauge causes glycogen storage].
abstract: Mutation in PRKAG2 encoding the gamma2 subunit of the AMP activated protein kinase (AMPK) cause human cardiomyopathy characterized by hypertrophy, Wolff-Parkinson-White syndrome, conduction system disease and glycogen storage in the myocardium. AMPK is a master metabolic regulator activated by hormones and energy deficient states. A heterotrimer enzyme comprising the catalytic alpha- and regulatory beta-and gamma-subunits was preserved through evolution and is ubiquitously expressed among mammalian tissues. AMPK is activated by AMP and inhibited by ATP that competes for binding to the regulatory sites on the gamma-subunit. Upstream kinases which phosphorylate Thr172 on the catalytic subunit activate the enzyme during exercise, ischemia, in response to sympathetic stimulation and hormones such as leptin and adiponectin. AMPK operates by phosphorylating its target proteins such as Acetyl CoA Carboxylase. Its classic functions include decreased fat synthesis in liver and adipose tissues, increased fatty acid oxidation, stimulating muscle glucose uptake and glycolysis. Altogether, these activities serve to restore the cellular and whole body energy balance. Human mutations which disrupt the nucleotide-binding affinity of the gamma2 subunit lead to loss of inhibition by ATP and inappropriate activate AMPK under resting conditions. As a result, myocytes recruit energy metabolites in excess of demand, causing storage of glycogen. Will AMPK ever emerge as a therapeutic target? Bench experiments suggest its potential in treating diabetes, ischemia and cell cycle regulation but much work is needed until these developments reach the bedside.
authors.affiliation: The Cardiac Research Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva.
authors.forename: Michal
authors.initials: M
authors.lastname: Ofir
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
authors.forename: Bernardo A
authors.initials: BA
authors.lastname: Vidne
authors.forename: Dov
authors.initials: D
authors.lastname: Freimark
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
mesh_terms: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics*; D006008:Glycogen Storage Disease / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics
chemical_list: D009097:Multienzyme Complexes; D021122:Protein Subunits; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases