Your browser doesn't support javascript.
loading
Myosin binding protein-C phosphorylation is the principal mediator of protein kinase A effects on thick filament structure in myocardium.
Colson, Brett A; Patel, Jitandrakumar R; Chen, Peter P; Bekyarova, Tanya; Abdalla, Mohamed I; Tong, Carl W; Fitzsimons, Daniel P; Irving, Thomas C; Moss, Richard L.
Afiliação
  • Colson BA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53711, USA. bacolson@umn.edu
J Mol Cell Cardiol ; 53(5): 609-16, 2012 Nov.
Article em En | MEDLINE | ID: mdl-22850286
Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a regulator of pump function in healthy hearts. However, the mechanisms of regulation by cAMP-dependent protein kinase (PKA)-mediated cMyBP-C phosphorylation have not been completely dissociated from other myofilament substrates for PKA, especially cardiac troponin I (cTnI). We have used synchrotron X-ray diffraction in skinned trabeculae to elucidate the roles of cMyBP-C and cTnI phosphorylation in myocardial inotropy and lusitropy. Myocardium in this study was isolated from four transgenic mouse lines in which the phosphorylation state of either cMyBP-C or cTnI was constitutively altered by site-specific mutagenesis. Analysis of peak intensities in X-ray diffraction patterns from trabeculae showed that cross-bridges are displaced similarly from the thick filament and toward actin (1) when both cMyBP-C and cTnI are phosphorylated, (2) when only cMyBP-C is phosphorylated, and (3) when cMyBP-C phosphorylation is mimicked by replacement with negative charge in its PKA sites. These findings suggest that phosphorylation of cMyBP-C relieves a constraint on cross-bridges, thereby increasing the proximity of myosin to binding sites on actin. Measurements of Ca(2+)-activated force in myocardium defined distinct molecular effects due to phosphorylation of cMyBP-C or co-phosphorylation with cTnI. Echocardiography revealed that mimicking the charge of cMyBP-C phosphorylation protects hearts from hypertrophy and systolic dysfunction that develops with constitutive dephosphorylation or genetic ablation, underscoring the importance of cMyBP-C phosphorylation for proper pump function.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Processamento de Proteína Pós-Traducional / Proteínas Quinases Dependentes de AMP Cíclico / Troponina I / Miocárdio Tipo de estudo: Diagnostic_studies Limite: Animals Idioma: En Revista: J Mol Cell Cardiol Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Processamento de Proteína Pós-Traducional / Proteínas Quinases Dependentes de AMP Cíclico / Troponina I / Miocárdio Tipo de estudo: Diagnostic_studies Limite: Animals Idioma: En Revista: J Mol Cell Cardiol Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido