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- W2037805212 abstract "In normal heart, troponin I (TnI) phosphorylation alters myofibrillar Ca2+-sensitivity and increases the speed of Ca2+-dissociation (lusitropic effect). We have discovered several cases in human heart muscle (DCM mutations, HCM mutations, septal myectomy) where Ca2+-sensitivity is independent of TnI phosphorylation.The ACTC E361G DCM mutation had no effect upon Ca2+-sensitivity at all when tested in thin filaments containing donor heart troponin. However if troponin was dephosphorylated, the wild-type actin containing thin filaments had a higher Ca2+-sensitivity than ACTC E361G containing thin filaments. Thus, Ca2+-sensitivity is uncoupled from TnI phosphorylation. This was also observed with another 6 DCM mutations (TnT R141W, TnI K36Q, TnC G159D and Tm E40K and E54K).The ACTC E99K HCM mutation causes an increase in Ca2+-sensitivity, but uncoupling also occurs, as there is no difference in the Ca2+-sensitivity of ACTC E99K containing thin filaments with phosphorylated and dephosphorylated troponin. The uncoupling must be a direct effect of the mutation, which influences TnI properties allosterically.We have been studying myectomy samples as a source of human HCM tissue. The Ca2+-sensitivity of thin filaments with HOCM troponin was the same as donor heart troponin even though the TnI phosphorylation levels were very different. This uncoupling is independent of the mutation causing HCM so one of the troponin subunits is functionally abnormal. When HOCM troponin was exchanged with recombinant TnT there was a 1.9-fold higher Ca2+-sensitivity as was expected with the low level of phosphorylation. Therefore a change in TnT is responsible for the observed disruption of the Ca2+-sensitivity-phosphorylation relationship in human myectomy samples.Thus, the ‘uncoupling’ phenomenon seems to be a widespread consequence of cardiomyopathy and plays a key role in the pathogenesis of familial cardiomyopathy." @default.
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- W2037805212 date "2012-01-01" @default.
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- W2037805212 title "Does Uncoupling of Troponin I Phosphorylation from Changes in Myofibrillar Ca2+-Sensitivity Play a Role in the Pathogenesis of Cardiomyopathy?" @default.
- W2037805212 doi "https://doi.org/10.1016/j.bpj.2011.11.3033" @default.
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