Key result
Nav1.5 oligomerization involves direct alpha-subunit interactions and intermediary proteins that influence cardiomyocyte coupled gating.
Why the study?
The molecular mechanisms underlying single-molecule redistribution and biophysical cooperativity of Na v 1.5 within cardiomyocyte membrane microdomains remain not fully understood.
This review provides insights into the molecular mechanisms of Nav1.5 oligomerization and its role in cardiac cellular excitability and dominant-negative effects.
May guide SCN5A variant interpretation in channelopathies; leaves open functional validation of oligomerization in human myocardium.
Clusters of the α-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 α-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 α–α-subunit interactions and oligomerization through intermediary proteins such as Na v β-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.
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Iamshanova et al. (2023) conducted a review in Abnormal cardiac phenotypes. Na v 1.5 oligomerization was evaluated. Na v 1.5 oligomerization involves direct alpha-subunit interactions and intermediary proteins, with implications for coupled gating and dominant-negative effects in cardiomyocytes.
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