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Abstract
The cardiac voltage-gated sodium channel, Nav1.5, plays a central role in cardiac excitability and impulse propagation and associates with the dystrophin multiprotein complex at the lateral membrane of cardiomyocytes. It was previously shown that Nav1.5 protein content and the sodium current (lNa) were both decreased in cardiomyocytes of dystrophin-deficient mdx5cv mice. In this study, wild-type and mdx5cv mice were treated for 7 days with the proteasome inhibitor MG132 (10 μg/Kg/24 h) using implanted osmotic mini pumps. MG132 rescued both the total amount of Nav1.5 protein and lNa but, unlike in previous studies, de novo expression of dystrophin was not observed in skeletal or cardiac muscle. This study suggests that the reduced expression of Nav1.5 in dystrophin-deficient cells is dependent on proteasomal degradation.
Highlights
The cardiac voltage-gated sodium channel, Nav1.5, plays a central role in cardiac function as it is responsible for the depolarization of the cardiac action potential and propagation of cardiac electrical impulses (Nerbonne and Kass, 2005)
Using the dystrophin-deficient mouse model mdx5cv, we previously demonstrated that the absence of dystrophin in cardiomyocytes led to a ∼50% decrease in the total amount of Nav1.5 protein, which was associated with a ∼30% decrease in the cellular sodium current (INa)
THE PROTEASOME INHIBITOR MG132 RESCUES NAv1.5 PROTEIN LEVELS AND THE SODIUM CURRENT IN mdx5cv MICE The cardiac voltage-gated sodium channel, Nav1.5, is part of the dystrophin multiprotein complex (DMC) in mouse cardiomyocytes (Gavillet et al, 2006)
Summary
The cardiac voltage-gated sodium channel, Nav1.5, plays a central role in cardiac function as it is responsible for the depolarization of the cardiac action potential and propagation of cardiac electrical impulses (Nerbonne and Kass, 2005). Recent studies that have reported on Nav1.5 interacting partners have suggested that Nav1.5 may be part of distinct multiprotein complexes that differ between one cellular compartment and another, and that multiprotein complexes may be involved in the regulation of channel activity, cellular localization, and protein degradation (Tan et al, 2003; van Bemmelen et al, 2004; Mohler and Bennett, 2005; Albesa et al, 2011; Petitprez et al, 2011). Nav1.5 associates with the dystrophin multiprotein complex (DMC) at the lateral membrane of cardiomyocytes, as well as to the SAP97 protein at the intercalated disk of cardiac cells (Gee et al, 1998; Gavillet et al, 2006; Albesa et al, 2011; Petitprez et al, 2011). We demonstrated that in the HEK293 cell line the Nav1.5 channel is down-regulated to its ubiquitylation via the ubiquitin ligase activity of Nedd (van Bemmelen et al, 2004; Rougier et al, 2005)
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