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Mutations in voltage-gated Na channels have been linked to several channelopathies leading to a wide variety of diseases including cardiac arrhythmias, epilepsy, and myotonia. We have previously demonstrated that voltage-gated Na channel (Na)1.5 trafficking-deficient mutant channels could lead to a dominant negative effect by impairing trafficking of the wild-type (WT) channel. We also reported that voltage-gated Na channels associate as dimers with coupled gating properties. Here, we hypothesized that the dominant negative effect of mutant Na channels could also occur through coupled gating. This was tested using cell surface biotinylation and single channel recordings to measure the gating probability and coupled gating of the dimers. As previously reported, coexpression of Na1.5-L325R with WT channels led to a dominant negative effect, as reflected by a 75% reduction in current density. Surprisingly, cell surface biotinylation showed that Na1.5-L325R mutant is capable of trafficking, with 40% of Na1.5-L325R reaching the cell surface when expressed alone. Importantly, even though a dominant negative effect on the Na current is observed when WT and Na1.5-L325R are expressed together, the total Na channel cell surface expression was not significantly altered compared with WT channels alone. Thus, the trafficking deficiency could not explain the 75% decrease in inward Na current. Interestingly, single channel recordings showed that Na1.5-L325R exerted a dominant negative effect on the WT channel at the gating level. Both coupled gating and gating probability of WT:L325R dimers were drastically impaired. We conclude that dominant negative suppression exerted by Na1.5 mutants can also be caused by impairing the WT gating probability, a mechanism resulting from the dimerization and coupled gating of voltage-gated Na channel α-subunits. NEW & NOTEWORTHY The presence of dominant negative mutations in the Na channel gene leading to Brugada syndrome was supported by our recent findings that Na channel α-subunits form dimers. Up until now, the dominant negative effect was thought to be caused by the interaction of the wild-type Na channel with trafficking-deficient mutant channels. However, the present study demonstrates that coupled gating of voltage-gated Na channels can also be responsible for the dominant negative effect leading to arrhythmias.
Download full-text PDF |
Source |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297814 | PMC |
http://dx.doi.org/10.1152/ajpheart.00721.2017 | DOI Listing |
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