Capsaicin as an amphipathic modulator of NaV1.5 mechanosensitivity. Issue 1 (31st December 2022)

• Record Type: Journal Article
• Authors: Cowan, Luke M.; Strege, Peter R.; Rusinova, Radda; Andersen, Olaf S.; Farrugia, Gianrico; Beyder, Arthur
• Is Part Of: Channels. Volume 16:Issue 1(2022)
• Page Start: 9
• Page End: 26
• Publication Date: 2022-12-31
• Subjects: Amphipathic -- arrhythmia -- capsaicin -- electrophysiology -- functional gastrointestinal disorder -- ion channel -- irritable bowel syndrome -- mechanosensitivity -- mechanotransduction -- voltage-gated sodium channel type 5; Ion channels -- Periodicals; 572.3
• DOI: 10.1080/19336950.2022.2026015
• Languages: English
• ISSNs: 1933-6950

Abstract

ABSTRACT: SCN5A -encoded NaV 1.5 is a voltage-gated Na + channel that drives the electrical excitability of cardiac myocytes and contributes to slow waves of the human gastrointestinal smooth muscle cells. NaV 1.5 is mechanosensitive: mechanical force modulates several facets of NaV 1.5's voltage-gated function, and some NaV 1.5 channelopathies are associated with abnormal NaV 1.5 mechanosensitivity (MS). A class of membrane-active drugs, known as amphiphiles, therapeutically target NaV 1.5's voltage-gated function and produce off-target effects including alteration of MS. Amphiphiles may provide a novel option for therapeutic modulation of NaV 1.5's mechanosensitive operation. To more selectively target NaV 1.5 MS, we searched for a membrane-partitioning amphipathic agent that would inhibit MS with minimal closed-state inhibition of voltage-gated currents. Among the amphiphiles tested, we selected capsaicin for further study. We used two methods to assess the effects of capsaicin on NaV 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 NaV 1.5 MS by examining macro-patch and whole-cell Na + current parameters with and without force. Capsaicin abolished the pressure- and shear-mediated peak current increase and acceleration; and the mechanosensitive shifts in the voltage-dependence of activation (shear) and inactivation (pressure and shear). Exploring the recovery from inactivation and use-dependent entry into inactivation, we found divergent stimulus-dependent effects that could potentiate or mitigate the effect of capsaicin, suggesting that mechanical stimuli may differentially modulate NaV 1.5 MS. We conclude that selective modulation of NaV 1.5 MS makes capsaicin a promising candidate for therapeutic interventions targeting MS.