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- W2377025170 abstract "We recently demonstrated that cardiac sodium channels (Nav1.5) localized within gap junction (GJ) -adjacent microdomains within the intercalated disc (ID) may enable ephaptic coupling between cardiac myocytes. Further we demonstrated conduction slowing and elevated arrhythmia risk secondary to disruption of close membrane apposition (<10nm) within these microdomains. Confocal micrographs of guinea pig ventricular myocardium revealed expression of β1 (SCN1b), a sodium channel auxiliary subunit and cell adhesion molecule, throughout the interplicate regions of the ID. Therefore, we hypothesized that β1-mediated adhesion may be key to close membrane apposition within Nav1.5-rich ID microdomains and thereby, to ephaptic coupling. In order to assess β1-localization within the ID, we analyzed STORM images of guinea pig ventricular sections immunolabeled for β1 along with Cx43 and N-cadherin (N-Cad) using custom algorithms. Overall, 16±2% of Cx43 clusters overlapped with a β1 cluster while 30±3% had a β1 cluster <200nm away, with a median distance of 55±6nm between Cx43 and β1. In contrast, only 7±3% of N-Cad overlapped with β1 while 16±2% had β1 <200nm away (p<0.05 vs. Cx43-β1), with a median distance of 154±98nm between N-Cad and β1. These data suggest preferential β1 localization adjacent Cx43 GJ relative (interplicate ID regions) to N-cadherin (plicate ID regions). Next we examined β1-mediated adhesion using electric cell-substrate impedance spectroscopy (ECIS): 1610 cells heterologously overexpressing β1 revealed 3-fold higher barrier function relative to native 1610 cells. Further, βadp1, a peptide mimetic of the β1 adhesion domain, inhibited barrier function in dose dependent fashion in β1-overexpressing 1610 cells but not in native 1610 cells. Taken together our results support a role for β1-mediated adhesion in modulating ephaptic coupling in the heart and highlight it as a potential target for novel anti-arrhythmic therapy." @default.
- W2377025170 created "2016-06-24" @default.
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- W2377025170 date "2016-02-01" @default.
- W2377025170 modified "2023-09-28" @default.
- W2377025170 title "Novel Storm-Based Quantitative Assessment of Relative Protein Localization Reveals New Role for Sodium Channel β1 Subunit in Cardiac Conduction" @default.
- W2377025170 doi "https://doi.org/10.1016/j.bpj.2015.11.650" @default.
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