Capsaicin alters human NaV1.5 mechanosensitivity

Abstract

ABSTRACTSCN5A-encoded NaV1.5 is a voltage-gated Na+ channel expressed in cardiac myocytes and human gastrointestinal (GI) smooth muscle cells (SMCs). NaV1.5 contributes to electrical excitability in the heart and slow waves in the gut. NaV1.5 is also mechanosensitive, and mechanical force modulates several modes of NaV1.5’s voltage-dependent function. NaV1.5 mutations in patients with cardiac arrhythmias and gastrointestinal diseases lead to abnormal mechano- and voltage-sensitivity. Membrane permeable amphipathic drugs that target NaV1.5 in the heart and GI tract alter NaV1.5 mechanosensitivity (MS), suggesting that amphipaths may be a viable therapeutic option for modulating NaV1.5 function. We therefore searched for membrane-permeable amphipathic agents that would modulate NaV1.5 MS with minimal effect on NaV1.5 voltage-gating intact to more selectively target mechanosensitivity. We used two methods to assess NaV1.5 MS: (1) membrane suction in cell-attached macroscopic patches and (2) fluid shear stress on whole cells. We tested the effect of capsaicin on NaV1.5 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-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 NaV1.5 MS. We conclude that selective modulation of MS makes capsaicin is a novel modulator of NaV1.5 MS and a promising therapeutic candidate.