Background: In cardiac ventricular muscle cells, the presence of voltage-gated sodium channels Na_v1.5 at the lateral membrane depends in part on the interaction between the dystrophin-syntrophin complex and the Na_v1.5 C-terminal PDZ-domain-binding sequence Ser-Ile-Val (SIV motif). α1-Syntrophin, a PDZ-domain adaptor protein, mediates the interaction between Na_v1.5 and dystrophin at the lateral membrane of cardiac cells. Using the cell-attached patch-clamp approach on cardiomyocytes expressing Na_v1.5 in which the SIV motif is deleted (ΔSIV), sodium current (I_Na) recordings from the lateral membrane revealed a SIV-motif-independent I_Na. Since immunostaining has suggested that Na_v1.5 is expressed in transverse (T-) tubules, this remaining I_Na might be carried by channels in the T-tubules. Of note, a recent study using heterologous expression systems showed that α1-syntrophin also interacts with the Na_v1.5 N-terminus, which may explain the SIV-motif independent I_Na at the lateral membrane of cardiomyocytes. Aim: To address the role of α1-syntrophin in regulating the I_Na at the lateral membrane of cardiac cells. Methods and Results: Patch-clamp experiments in cell-attached configuration were performed on the lateral membranes of wild-type, α1-syntrophin knockdown, and ΔSIV ventricular mouse cardiomyocytes. Compared to wild-type, a reduction of the lateral I_Na was observed in myocytes from α1-syntrophin knockdown hearts. Similar to ΔSIV myocytes, a remaining I_Na was still recorded. In addition, cell-attached I_Na recordings from lateral membrane did not differ significantly between non-detubulated and detubulated ΔSIV cardiomyocytes. Lastly, we obtained evidence suggesting that cell-attached patch-clamp experiments on the lateral membrane cannot record currents carried by channels in T-tubules such as calcium channels. Conclusion: Altogether, these results suggest the presence of a sub-pool of sodium channels at the lateral membrane of cardiomyocytes that is independent of α1-syntrophin and the PDZ-binding motif of Na_v1.5, located in membrane domains outside of T-tubules. The question of a T-tubular pool of Na_v1.5 channels, however, remains open.

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