Exploring the Oligomerization of Na_v1.5 and Its Implication for the Dominant-Negative Effect

Clusters of the & alpha;-subunit of voltage-gated sodium (Na-v) channels have been observed in various tissues and are recognized as key regulators of cellular excitability and action potential propagation. In cardiomyocytes, the most abundant Na-v & alpha;-subunit, Na(v)1.5, is expressed at specialized membrane microdomains within the intercalated disk and lateral membrane. Although Na(v)1.5 remodeling within these microdomains could cause abnormal cardiac phenotypes, the molecular mechanisms underlying single-molecule redistribution and biophysical cooperativity of Na(v)1.5 remain not fully understood. This review summarizes the current knowledge on the oligomerization of Na(v)1.5. In particular, direct & alpha;-& alpha;-subunit interactions and oligomerization through intermediary proteins such as Na-v & beta;-subunits and 14-3-3 proteins are discussed. The possible implication of Na(v)1.5 oligomerization in the coupled gating in cis and trans conformations as well as in the dominant-negative effect is reviewed.