SCN5A is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel Na_V1.5. The influx of Na⁺ through Na_V1.5 produces a fast depolarization in membrane potential, indispensable for electrical excitability in cardiomyocytes and important for electrical slow waves in GI smooth muscle. As such, abnormal Na_V1.5 voltage gating or mechanosensitivity may result in channelopathies. SCN5A mutation G615E – found separately in cases of acquired long-QT syndrome, sudden cardiac death, and irritable bowel syndrome – has a relatively minor effect on Na_V1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-Na_V1.5 in HEK-293 cells was examined by shear stress on voltage- or current-clamped whole cells or pressure on macroscopic patches. Unlike WT, voltage-clamped G615E-Na_V1.5 showed a loss in shear- and pressure-sensitivity of peak current yet a normal leftward shift in the voltage-dependence of activation. In current-clamp, shear stress led to a significant increase in firing spike frequency with a decrease in firing threshold for WT but not G615E-Na_V1.5. Our results show that the G615E mutation leads to functionally abnormal Na_V1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology.

SCN5A作为电压门控机械敏感钠通道Na _V 1.5在心肌细胞和胃肠道（GI）平滑肌细胞（SMC）中表达。Na ⁺通过Na _V 1.5的流入使膜电位快速去极化，这对于心肌细胞的电兴奋性必不可少，并且对于GI平滑肌的电慢波也很重要。因此，异常的Na _V 1.5电压门控或机械敏感性可能会导致通道病。SCN5A突变G615E-在获得性长QT综合征，心源性猝死和肠易激综合征中单独发现-对Na _V的影响相对较小1.5电压门控。这项研究的目的是测试G615E是否会影响机械敏感性。HEK-293细胞中野生型（WT）或G615E-Na _V 1.5的机械敏感性通过电压或电流固定的全细胞上的剪切应力或宏观斑片上的压力来检查。与WT不同，电压钳制的G615E-Na _V 1.5在峰值电流的切变和压力敏感性方面有所降低，但在激活电压依赖性方面却出现了正常的向左移动。在电流钳中，剪切应力导致点火尖峰频率显着增加，而WT的点火阈值降低，但G615E-Na _V 1.5则不然。我们的结果表明，G615E突变导致功能异常的Na _V1.5个通道，这些通道会导致机械敏感性和机械电反馈中断，并暗示可能对平滑肌的病理生理产生影响。