Capsaicin alters human Na V 1.5 mechanosensitivity

作者：Luke M. Cowan, Peter R. Strege, Radda Rusinova, Olaf S. Andersen, Arthur Beyder, Gianrico Farrugia · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2021 · DOI：10.1101/2021.07.13.452086 · 被引用次数：1 · 研究领域：Ion channel regulation and function、Erythrocyte Function and Pathophysiology、Ion Channels and Receptors

ABSTRACT SCN5A -encoded Na V 1.5 is a voltage-gated Na + channel expressed in cardiac myocytes and human gastrointestinal (GI) smooth muscle cells (SMCs). Na V 1.5 contributes to electrical excitability in the heart and slow waves in the gut. Na V 1.5 is also mechanosensitive, and mechanical force modulates several modes of Na V 1.5’s voltage-dependent function. Na V 1.5 mutations in patients with cardiac arrhythmias and gastrointestinal diseases lead to abnormal mechano- and voltage-sensitivity. Membrane permeable amphipathic drugs that target Na V 1.5 in the heart and GI tract alter Na V 1.5 mechanosensitivity (MS), suggesting that amphipaths may be a viable therapeutic option for modulating Na V 1.5 function. We therefore searched for membrane-permeable amphipathic agents that would modulate Na V 1.5 MS with minimal effect on Na V 1.5 voltage-gating intact to more selectively target mechanosensitivity. We used two methods to assess Na V 1.5 MS: (1) membrane suction in cell-attached macroscopic patches and (2) fluid shear stress on whole cells. We tested the effect of capsaicin on Na V 1.5 MS by examining macropatch and whole-cell Na + current parameters with and without force. The pressure- and shear-mediated peak current increase and acceleration were effectively abolished by capsaicin. Capsaicin abolished the mechanosensitive shifts in the voltage-dependence of activation (shear) and inactivation (pressure and shear). Exploring the recovery from inactivation and use-depe...