Combining Super-Resolution Microscopy with Functional Nonoelectrophysiology to Gain Insight into Nanoscale Structural Physiology in Health and Disease

This is the authors' abstract. We don't add key points for this paper.

Regulation of voltage-gated Na+ channels (NaVs) is fundamental process that drives depolarization required for electrical signaling in excitable tissues. Within the membrane, NaVs function as either individual, non-interacting channels or assemble into multi-channel clusters. Growing evidence indicates that interactions among NaVs within clusters can potentially influence their biophysical properties and behavior. Assessment of clustering behavior has relied on either whole cell or cell-attached patch-clamp electrophysiology but these approaches are often limited to assessment of ensemble behavior of all channels, independent whether they were part of a cluster or not, or lack the molecular context that that would contextualize the biophysical behavior of single or multi-channel clusters. Recently, in collaboration with colleagues at the Ohio State University we have correlated local NaV activity using the remarkable localization precision of the scanning ion conductance microscopy combined with cell-attached patch-clamp capability with the underlying molecular distribution of NaVs as determined by STORM [1,2]. These findings highlight the critical role NaV clustering has in normal functioning of excitable tissue, whereas disruption of these clusters can contribute to pathological conditions, including cardiac arrhythmias [1-3]. Current research is focused on understanding how clustering affects channel gating and pharmacological response, and clustering of these channels is impacted in health and disease using a combination of nanoelectrophysiology and MINFLUX nanoscopy [4]. Combination of these novel approaches will illuminate the molecular structure-function relationships in excitable tissue in novel ways. These, in turn, will provide novel insights into disease mechanisms and will help inform the development of targeted therapeutic strategies.