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

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.