Na v 1.5 single-molecule localization reveals different reorganization modes at cardiomyocyte domains

Mutations in the gene encoding the sodium channel Na1.5 cause various cardiac arrhythmias. This variety may arise from different determinants of Na1.5 expression between cardiomyocyte domains. At the lateral membrane and T-tubules, Na1.5 localization and function remain insufficiently characterized. We used novel single-molecule localization microscopy (SMLM) and modeling to define nanoscale features of Na1.5 localization and distribution at the lateral membrane, groove, and T-tubules in wild-type, dystrophin-deficient () mice, and mice expressing C-terminally truncated Na1.5 (ΔSIV). We show that Na1.5 organizes as distinct clusters in the groove and T-tubules which density and distribution partially depend on SIV and dystrophin. We found that overall reduction in Na1.5 expression in and ΔSIV cells results in a non-uniform redistribution with Na1.5 being specifically reduced at the groove of ΔSIV and increased in T-tubules of cardiomyocytes. Na1.5 mutations may therefore site-specifically affect Na1.5 localization and distribution depending on site-specific interacting proteins.