Fast opening and closing of voltage-gated sodium channels are crucial for proper propagation of the action potential through excitable tissues. Unlike potassium channels, sodium channel α-subunits are believed to form functional monomers. Yet, an increasing body of literature shows inconsistency with the traditional idea of a single α-subunit functioning as a monomer. Here we demonstrate that sodium channel α-subunits not only physically interact with each other but they actually assemble, function and gate as a dimer. We identify the region involved in the dimerization and demonstrate that 14-3-3 protein mediates the coupled gating. Importantly we show conservation of this mechanism among mammalian sodium channels. Our study not only shifts conventional paradigms in regard to sodium channel assembly, structure, and function but importantly this discovery of the mechanism involved in channel dimerization and biophysical coupling could open the door to new approaches and targets to treat and/or prevent sodium channelopathies.

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Background Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A, the gene encoding for the pore-forming α-subunit of the cardiac sodium channel. Typically, BrS mutations in SCN5A result in a reduction of sodium current with some mutations even exhibiting a dominant-negative effect on wild-type (WT) channels thus leading to an even more prominent decrease in current amplitudes. However, there is also a category of apparently benign (“atypical”) BrS SCN5A mutations that in vitro demonstrates only minor biophysical defects. It is therefore not clear how these mutations produce a BrS phenotype. We hypothesized that similar to dominant-negative mutations atypical mutations could lead to a reduction in sodium currents when co-expressed with WT to mimic the heterozygous patient genotype. Methods and Results WT and “atypical” BrS mutations were co-expressed in HEK293 cells, showing a reduction in sodium current densities similar to typical BrS mutations. Importantly, this reduction in sodium current was also seen when the atypical mutations were expressed in rat or human cardiomyocytes. This decrease in current density was the result of reduced surface expression of both mutant and WT channels. Conclusions Taken together, we have shown how apparently benign SCN5A BrS mutations can lead to the ECG abnormalities seen in BrS patients through an induced defect that is only present when the mutations are co-expressed with WT channels. Our work has implications for risk management and stratification for some SCN5A-implicated BrS patients.