Nanoscale organization in the cell membrane dynamically modulates the biophysics of voltage-gated sodium channels

Precise regulation of ion channel biophysics is an essential life process
that governs electrical signaling in excitable tissues. Many ion channels
including voltage-gated Na+ channels (NaVs) exist in the membrane as
clusters, which show distinct biophysical behavior not predicted by
single-channel measurements. In both heterologous and native systems, we
report that single-channel-based predictions significantly overestimated
Na+ current (INa) amplitudes from multi-channel clusters. Computational
modeling suggested that these observations could reflect interactions
between adjacent channels, such as recently reported between NaVs, and
identified specific biophysical consequences thereof. This updated model
not only accurately predicted behaviors observed from NaV clusters and
consequent cellular physiology, but also suggested the possibility that
clustered NaVs may respond differently to use-dependent pharmacological
agents. Experiments validated the latter prediction and further identified
modulation of clustering as a novel approach to correcting macroscopic
electrophysiological dysfunction resulting from NaV defects linked to
life-threatening arrhythmias and seizures. Thus, our study not only
motivates a fundamental revision of how ion channels behave when clustered
but also highlights resulting biophysical effects as important
considerations for pharmacology and a potential therapeutic target to
address human disease.