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, Ca2+-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 Ca2+-sensitivity. We conclude that this DCM mutant significantly blunts the contractile response to phosphorylation and this novel mechanism may contribute to its pathogenic effect. (c) 2007 Elsevier Inc. All rights reserved.