Capsaicin as an amphipathic modulator of Na(V)1.5 mechanosensitivity.
Capsaicin as an amphipathic modulator of Na(V)1.5 mechanosensitivity.
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DOI：
10.1080/19336950.2022.2026015
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发表时间：
2022-12
期刊：
影响因子：
3.3
通讯作者：
Beyder, Arthur
中科院分区：
文献类型：
--
作者：
Cowan, Luke M.;Strege, Peter R.;Rusinova, Radda;Andersen, Olaf S.;Farrugia, Gianrico;Beyder, Arthur
关键词：
SCN5A编码的NaV1.5是一种电压门控的Na+通道，它驱动心肌细胞的电兴奋性，并有助于人类胃肠道平滑肌细胞的慢波。NaV1.5是机械敏感的：机械力调制NaV1.5的S电压门控功能的多个方面，一些NaV1.5通道病变与NaV1.5机械敏感性(MS)异常有关。一类膜活性药物，称为两亲性药物，靶向于NaV1.5‘S的电压门控功能，并产生包括MS改变在内的非靶点效应，可能为NaV1.5’S机械敏感手术的治疗调控提供一种新的选择。为了更有选择性地靶向NaV1.5-MS，我们寻找了一种膜分区两亲性试剂，它可以在最小限度地闭合抑制电压门控电流的情况下抑制MS。在测试的两亲化合物中，我们选择了辣椒素进行进一步研究。我们使用两种方法来评估辣椒素对NaV1.5-MS的影响：(1)细胞附着的宏观斑块中的膜吸力和(2)整个细胞上的流体剪应力。我们通过检测有无作用力的大片和全细胞Na+电流参数来检测辣椒素对NaV1.5-MS的影响。辣椒素消除了压力和剪切介导的峰值电流增加和加速，以及激活(剪切)和失活(压力和剪切)电压依赖性的机械敏感位移。在探索从失活和使用依赖进入失活的过程中，我们发现了不同的刺激依赖效应，可以增强或减轻辣椒素的影响，这表明机械刺激可能对MS的NaV1.5进行不同的调制。我们得出结论，对NaV1.5-MS的选择性调制使辣椒素成为针对MS的治疗干预的有前景的候选药物。
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.
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影响因子：
3.3
作者：
Banderali, Umberto;Juranka, Peter F.;Morris, Catherine E.
通讯作者：
Morris, Catherine E.
影响因子：
3.5
作者：
Beyder A;Gibbons SJ;Mazzone A;Strege PR;Saravanaperumal SA;Sha L;Higgins S;Eisenman ST;Bernard CE;Geurts A;Kline CF;Mohler PJ;Farrugia G
通讯作者：
Farrugia G
影响因子：
1.9
作者：
ABRAHAMSSON, H;DOTEVALL, G
通讯作者：
DOTEVALL, G
DOI：
10.1016/s0735-1097(83)80338-6
发表时间：
1983-01-01
影响因子：
24
作者：
GREENE, HL;GRAHAM, EL;TROBAUGH, GB
通讯作者：
TROBAUGH, GB
影响因子：
3.4
作者：
Aniwan S;Gonlachanvit S
通讯作者：
Gonlachanvit S