Clusters of the α-subunit of voltage-gated sodium (Nav) 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 Nav α-subunit, Nav1.5, is expressed at specialized membrane microdomains within the intercalated disk and lateral membrane. Although Nav1.5 remodeling within these microdomains could cause abnormal cardiac phenotypes, the molecular mechanisms underlying single-molecule redistribution and biophysical cooperativity of Nav1.5 remain not fully understood. This review summarizes the current knowledge on the oligomerization of Nav1.5. In particular, direct α–α-subunit interactions and oligomerization through intermediary proteins such as Navβ-subunits and 14–3–3 proteins are discussed. The possible implication of Nav1.5 oligomerization in the coupled gating in cis and trans conformations as well as in the dominant-negative effect is reviewed.
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