title: Differential thermosensitivity in mixed syndrome cardiac sodium channel mutants.
abstract: Cardiac arrhythmias are often associated with mutations in SCN5A the gene that encodes the cardiac paralogue of the voltage-gated sodium channel, NaV 1.5. The NaV 1.5 mutants R1193Q and E1784K give rise to both long QT and Brugada syndromes. Various environmental factors, including temperature, may unmask arrhythmia. We sought to determine whether temperature might be an arrhythmogenic trigger in these two mixed syndrome mutants. Whole-cell patch clamp was used to measure the biophysical properties of NaV 1.5 WT, E1784K and R1193Q mutants. Recordings were performed using Chinese hamster ovary (CHOk1) cells transiently transfected with the NaV 1.5 α subunit (WT, E1784K, or R1193Q), β1 subunit, and eGFP. The channels' voltage-dependent and kinetic properties were measured at three different temperatures: 10ºC, 22ºC, and 34ºC. The E1784K mutant is more thermosensitive than either WT or R1193Q channels. When temperature is elevated from 22°C to 34°C, there is a greater increase in late INa and use-dependent inactivation in E1784K than in WT or R1193Q. However, when temperature is lowered to 10°C, the two mutants show a decrease in channel availability. Action potential modelling using Q10 fit values, extrapolated to physiological and febrile temperatures, show a larger transmural voltage gradient in E1784K compared to R1193Q and WT with hyperthermia. The E1784K mutant is more thermosensitive than WT or R1193Q channels. This enhanced thermosensitivity may be a mechanism for arrhythmogenesis in patients with E1784K sodium channels.
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada, V5A 1S6.
authors.forename: Mena
authors.initials: M
authors.lastname: Abdelsayed
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada, V5A 1S6.
authors.forename: Colin H
authors.initials: CH
authors.lastname: Peters
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada, V5A 1S6.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Ruben
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D053840:Brugada Syndrome / Q000235:genetics*; D016466:CHO Cells; D000075224:Cardiac Conduction System Disease; D002460:Cell Line; D003412:Cricetulus; D005334:Fever / Q000235:genetics; D006321:Heart / Q000503:physiopathology*; D006329:Heart Conduction System / Q000002:abnormalities*; D008133:Long QT Syndrome / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel