mutation G615E results in Na1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity.

Author(s) Strege, P.R.; Mercado-Perez, A.; Mazzone, A.; Saito, Y.A.; Bernard, C.E.; Farrugia, G.; Beyder, A.
Journal Channels (Austin)
Date Published 2019 Dec

is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel Na1.5. The influx of Na through Na1.5 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 Na1.5 voltage gating or mechanosensitivity may result in channelopathies. mutation G615E - found separately in cases of acquired long-QT syndrome, sudden cardiac death, and irritable bowel syndrome - has a relatively minor effect on Na1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-Na1.5 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-Na1.5 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-Na1.5. Our results show that the G615E mutation leads to functionally abnormal Na1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology.

DOI 10.1080/19336950.2019.1632670
ISSN 1933-6969
Citation Channels (Austin). 2019;13(1):287298.