DCM troponin C mutant Gly159Asp blunts the response to troponin phosphorylation.
Dilated cardiomyopathy (DCM) can be caused by a Gly159Asp mutation in cardiac troponin C (cTnC). Our previous work found that partial replacement of endogenous troponin in skinned muscle fibres with human cardiac troponin containing Gly159Asp cTnC had no significant effect on maximum force generation, Ca(2+)-sensitivity or cooperativity, but halved the activation rate. In order to examine whether the mutant affected contractility when troponin was phosphorylated, Gly159Asp cTnC was introduced in the presence of a phosphomimic of protein kinase A phosphorylation of troponin I (Ser23Asp,Ser24Asp). The increased force production of the muscle fibres caused by this phosphomimic was significantly depressed. Furthermore, in the presence of the protein kinase C phosphomimic of troponin T (Thr203Glu), Gly159Asp mutant significantly reversed the decrease in Ca(2+)-sensitivity. We conclude that this DCM mutant significantly blunts the contractile response to phosphorylation and this novel mechanism may contribute to its pathogenic effect.
Preston
Laura C
LC
Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre of Human Genetics, Oxford OX3 7BN, UK.
Ashley
Christopher C
CC
Redwood
Charles S
CS
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007537:Isometric Contraction / Q000502:physiology*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011817:Rabbits; D014336:Troponin / Q000235:genetics / Q000378:metabolism*
D014336:Troponin