{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":46,"searchCount":0},"additional":{"submitter":["Strege PR"],"funding":["NIDDK NIH HHS","National Institute of Diabetes and Digestive and Kidney Diseases","American Gastroenterological Association"],"pagination":["287-298"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6629189"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13(1)"],"pubmed_abstract":["<i>SCN5A</i> is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel Na<sub>V</sub>1.5. The influx of Na<sup>+</sup> through Na<sub>V</sub>1.5 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<sub>V</sub>1.5 voltage gating or mechanosensitivity may result in channelopathies. <i>SCN5A</i> 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<sub>V</sub>1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-Na<sub>V</sub>1.5 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<sub>V</sub>1.5 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<sub>V</sub>1.5. Our results show that the G615E mutation leads to functionally abnormal Na<sub>V</sub>1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology."],"journal":["Channels (Austin, Tex.)"],"pubmed_title":["<i>SCN5A</i> mutation G615E results in Na<sub>V</sub>1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity."],"pmcid":["PMC6629189"],"funding_grant_id":["RSA","DK119683","K23 DK066271","K08 DK106456","P30DK084567","P30 DK084567","DK106456","R01 DK052766","DK052766"],"pubmed_authors":["Strege PR","Saito YA","Bernard CE","Beyder A","Mazzone A","Farrugia G","Mercado-Perez A"],"view_count":["46"],"additional_accession":[]},"is_claimable":false,"name":"<i>SCN5A</i> mutation G615E results in Na<sub>V</sub>1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity.","description":"<i>SCN5A</i> is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel Na<sub>V</sub>1.5. The influx of Na<sup>+</sup> through Na<sub>V</sub>1.5 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<sub>V</sub>1.5 voltage gating or mechanosensitivity may result in channelopathies. <i>SCN5A</i> 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<sub>V</sub>1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-Na<sub>V</sub>1.5 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<sub>V</sub>1.5 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<sub>V</sub>1.5. Our results show that the G615E mutation leads to functionally abnormal Na<sub>V</sub>1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Dec","modification":"2024-02-15T05:17:05.234Z","creation":"2019-07-25T07:10:03Z"},"accession":"S-EPMC6629189","cross_references":{"pubmed":["31262209"],"doi":["10.1080/19336950.2019.1632670"]}}