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ABSTRACT: Background
Mutations in the gene encoding the cardiac voltage-gated sodium channel Nav1.5 cause various cardiac arrhythmias. This variety may arise from different determinants of Nav1.5 expression between cardiomyocyte domains. At the lateral membrane and T-tubules, Nav1.5 localization and function remain insufficiently characterized.Methods
We used novel single-molecule localization microscopy and computational modeling to define nanoscale features of Nav1.5 localization and distribution at the lateral membrane, the lateral membrane groove, and T-tubules in cardiomyocytes from wild-type (N=3), dystrophin-deficient (mdx; N=3) mice, and mice expressing C-terminally truncated Nav1.5 (ΔSIV; N=3). We moreover assessed T-tubules sodium current by recording whole-cell sodium currents in control (N=5) and detubulated (N=5) wild-type cardiomyocytes.Results
We show that Nav1.5 organizes as distinct clusters in the groove and T-tubules which density, distribution, and organization partially depend on SIV and dystrophin. We found that overall reduction in Nav1.5 expression in mdx and ΔSIV cells results in a nonuniform redistribution with Nav1.5 being specifically reduced at the groove of ΔSIV and increased in T-tubules of mdx cardiomyocytes. A T-tubules sodium current could, however, not be demonstrated.Conclusions
Nav1.5 mutations may site-specifically affect Nav1.5 localization and distribution at the lateral membrane and T-tubules, depending on site-specific interacting proteins. Future research efforts should elucidate the functional consequences of this redistribution.
SUBMITTER: Vermij SH
PROVIDER: S-EPMC7368852 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Circulation. Arrhythmia and electrophysiology 20200615 7
<h4>Background</h4>Mutations in the gene encoding the cardiac voltage-gated sodium channel Na<sub>v</sub>1.5 cause various cardiac arrhythmias. This variety may arise from different determinants of Na<sub>v</sub>1.5 expression between cardiomyocyte domains. At the lateral membrane and T-tubules, Na<sub>v</sub>1.5 localization and function remain insufficiently characterized.<h4>Methods</h4>We used novel single-molecule localization microscopy and computational modeling to define nanoscale featur ...[more]