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02948nam a2200325Ia 4500 |
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10-1080-19336950-2022-2026015 |
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220425s2022 CNT 000 0 und d |
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|a 19336950 (ISSN)
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|a Capsaicin as an amphipathic modulator of NaV1.5 mechanosensitivity
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|b Taylor and Francis Ltd.
|c 2022
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|a 18
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|z View Fulltext in Publisher
|u https://doi.org/10.1080/19336950.2022.2026015
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|a SCN5A-encoded NaV1.5 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. NaV1.5 is mechanosensitive: mechanical force modulates several facets of NaV1.5’s voltage-gated function, and some NaV1.5 channelopathies are associated with abnormal NaV1.5 mechanosensitivity (MS). A class of membrane-active drugs, known as amphiphiles, therapeutically target NaV1.5’s voltage-gated function and produce off-target effects including alteration of MS. Amphiphiles may provide a novel option for therapeutic modulation of NaV1.5’s mechanosensitive operation. To more selectively target NaV1.5 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 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 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 NaV1.5 MS. We conclude that selective modulation of NaV1.5 MS makes capsaicin a promising candidate for therapeutic interventions targeting MS. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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|a Amphipathic
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|a arrhythmia
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|a capsaicin
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|a electrophysiology
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|a functional gastrointestinal disorder
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|a ion channel
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|a irritable bowel syndrome
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|a mechanosensitivity
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|a mechanotransduction
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|a voltage-gated sodium channel type 5
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|a Andersen, O.S.
|e author
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|a Beyder, A.
|e author
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|a Cowan, L.M.
|e author
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|a Farrugia, G.
|e author
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|a Rusinova, R.
|e author
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|a Strege, P.R.
|e author
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773 |
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|t Channels
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