title: Characterization of the role of gamma2 R531G mutation in AMP-activated protein kinase in cardiac hypertrophy and Wolff-Parkinson-White syndrome.
abstract: AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a key role in the regulation of energy metabolism. In humans, mutations in the gamma2-subunit of AMPK cause cardiac hypertrophy associated with Wolff-Parkinson-White syndrome, characterized by ventricular preexcitation. The effect of these mutations on AMPK activity and in development of the disease is enigmatic. Here we report that transgenic mice with cardiac-specific expression of gamma2 harboring a mutation of arginine residue 531 to glycine (RG-TG) develop a striking cardiac phenotype by 4 wk of age, including hypertrophy, impaired contractile function, electrical conduction abnormalities, and marked glycogen accumulation. At this stage, AMPK activity isolated from hearts of RG-TG mice was almost completely abolished but could be restored after phosphorylation by an upstream AMPK kinase. At 1 wk of age, there was no detectable evidence of a cardiac phenotype, and AMPK activity in RG-TG hearts was similar to that in nontransgenic, control mice. We propose that mutations in gamma2 lead to suppression of total cardiac AMPK activity secondary to increased glycogen accumulation. The subsequent decrease in AMPK activity provides a mechanism that may explain the development of cardiac hypertrophy in this model.
authors.affiliation: Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Hammersmith Campus, Imperial College London, London W12 ONN, UK.
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Davies
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Wells
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Helen R
authors.initials: HR
authors.lastname: Whitrow
authors.forename: Tyrone D
authors.initials: TD
authors.lastname: Daniel
authors.forename: Robert
authors.initials: R
authors.lastname: Grignani
authors.forename: Craig A
authors.initials: CA
authors.lastname: Lygate
authors.forename: Jürgen E
authors.initials: JE
authors.lastname: Schneider
authors.forename: Gaëtane
authors.initials: G
authors.lastname: Noël
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: David
authors.initials: D
authors.lastname: Carling
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014927:Wolff-Parkinson-White Syndrome / Q000201:enzymology* / Q000235:genetics*
chemical_list: D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases