DCM troponin C mutant Gly159Asp blunts the response to troponin phosphorylation

Abstract

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.