Abstract
ABSTRACTKir2.x channels in ventricular cardiomyocytes (most prominently Kir2.1) account for the inward rectifier potassium current IK1, which controls the resting membrane potential and the final phase of action potential repolarization. Recently it was hypothesized that the dystrophin-associated protein complex (DAPC) is important in the regulation of Kir2.x channels. To test this hypothesis, we investigated potential IK1 abnormalities in dystrophin-deficient ventricular cardiomyocytes derived from the hearts of Duchenne muscular dystrophy mouse models. We found that IK1 was substantially diminished in dystrophin-deficient cardiomyocytes when compared to wild type myocytes. This finding represents the first functional evidence for a significant role of the DAPC in the regulation of Kir2.x channels.
Highlights
Duchenne muscular dystrophy (DMD), caused by mutations in the gene encoding for the cytoskeletal protein dystrophin, is a severe illness characterized by progressive muscle weakness and degeneration
Since ion channels in cardiomyocytes do not function in isolation, but instead in an orchestrated fashion as part of complex protein networks,[11,12] it is not surprising that dystrophin-deficiency impairs the properties of Nav1.5 channels
In order to test the hypothesis that the dystrophin-associated protein complex (DAPC) is important in the regulation of Kir2.x channels, here we have studied potential IK1 abnormalities in dystrophindeficient ventricular cardiomyocytes derived from DMD mouse models
Summary
Duchenne muscular dystrophy (DMD), caused by mutations in the gene encoding for the cytoskeletal protein dystrophin, is a severe illness characterized by progressive muscle weakness and degeneration. In affected patients this eventually leads to loss of ambulation, respiratory failure, and premature death. Dystrophin interacts with numerous proteins of the so-called dystrophin-associated protein complex (DAPC),[1,2] thereby serving as a linker between the cytoskeleton and the extracellular matrix Disruption of this link in case of dystrophin-deficiency renders muscle tissue vulnerable to mechanical stress.[3,4]. Syntrophin mutations were linked with an abnormal sodium current through Nav1.5 channels.[15]
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