Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.13 (
protein kinase C
)
49,245
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The
protein kinase C
(
PKC
) family is implicated in cardiac hypertrophy, contractile failure, and beta-adrenergic receptor (betaAR) dysfunction. Herein, we describe the effects of gain- and loss-of-
PKCalpha
function using transgenic expression of conventional
PKC
isoform translocation modifiers. In contrast to previously studied
PKC
isoforms, activation of
PKCalpha
failed to induce cardiac hypertrophy, but instead caused betaAR insensitivity and ventricular dysfunction.
PKCalpha
inhibition had opposite effects. Because
PKCalpha
is upregulated in human and experimental cardiac hypertrophy and failure, its effects were also assessed in the context of the Galphaq overexpression model (in which
PKCalpha
is transcriptionally upregulated). Normalization (inhibition) of
PKCalpha
activity in Galpha(q) hearts improved systolic and diastolic function, whereas further activation of
PKCalpha
caused a lethal
restrictive cardiomyopathy
with marked interstitial fibrosis. These results define pathological roles for
PKCalpha
as a negative regulator of ventricular systolic and diastolic function.
...
PMID:Protein kinase Calpha negatively regulates systolic and diastolic function in pathological hypertrophy. 1460 19
The cardiac troponin I (cTnI) R145W mutation is associated with
restrictive cardiomyopathy
(
RCM
). Recent evidence suggests that this mutation induces perturbed myofilament length-dependent activation (LDA) under conditions of maximal protein kinase A (PKA) stimulation. Some cardiac disease-causing mutations, however, have been associated with a blunted response to PKA-mediated phosphorylation; whether this includes LDA is unknown. Endogenous troponin was exchanged in isolated skinned human myocardium for recombinant troponin containing either cTnI R145W, PKA/
PKC
phosphomimetic charge mutations (S23D/S24D and T143E), or various combinations thereof. Myofilament Ca
2+
sensitivity of force, tension cost, LDA, and single myofibril activation/relaxation parameters were measured. Our results show that both R145W and T143E uncouple the impact of S23D/S24D phosphomimetic on myofilament function, including LDA. Molecular dynamics simulations revealed a marked reduction in interactions between helix C of cTnC (residues 56, 59, and 63), and cTnI (residue 145) in the presence of either cTnI
RCM
mutation or cTnI
PKC
phosphomimetic. These results suggest that the
RCM
-associated cTnI R145W mutation induces a permanent structural state that is similar to, but more extensive than, that induced by
PKC
-mediated phosphorylation of cTnI Thr-143. We suggest that this structural conformational change induces an increase in myofilament Ca
2+
sensitivity and, moreover, uncoupling from the impact of phosphorylation of cTnI mediated by PKA at the Ser-23/Ser-24 target sites. The R145W
RCM
mutation by itself, however, does not impact LDA. These perturbed biophysical and biochemical myofilament properties are likely to significantly contribute to the diastolic cardiac pump dysfunction that is seen in patients suffering from a
restrictive cardiomyopathy
that is associated with the cTnI R145W mutation.
...
PMID:Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres. 2755 62
