In:
Circulation: Arrhythmia and Electrophysiology, Ovid Technologies (Wolters Kluwer Health), Vol. 13, No. 7 ( 2020-07)
Abstract:
Mutations in the gene encoding the cardiac voltage-gated sodium channel Na v 1.5 cause various cardiac arrhythmias. This variety may arise from different determinants of Na v 1.5 expression between cardiomyocyte domains. At the lateral membrane and T-tubules, Na v 1.5 localization and function remain insufficiently characterized. Methods: We used novel single-molecule localization microscopy and computational modeling to define nanoscale features of Na v 1.5 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 Na v 1.5 (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 Na v 1.5 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 Na v 1.5 expression in mdx and ΔSIV cells results in a nonuniform redistribution with Na v 1.5 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: Na v 1.5 mutations may site-specifically affect Na v 1.5 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.
Type of Medium:
Online Resource
ISSN:
1941-3149
,
1941-3084
DOI:
10.1161/CIRCEP.119.008241
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
2425487-3
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