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Differential thermosensitivity in mixed syndrome cardiac sodium channel mutants
- Source :
- The Journal of Physiology. 593:4201-4223
- Publication Year :
- 2015
- Publisher :
- Wiley, 2015.
-
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.
- Subjects :
- Hyperthermia
0303 health sciences
Physiology
Chemistry
Chinese hamster ovary cell
Sodium channel
Mutant
Transfection
Anatomy
030204 cardiovascular system & hematology
medicine.disease
Green fluorescent protein
Cell biology
03 medical and health sciences
0302 clinical medicine
Cell culture
medicine
Patch clamp
030304 developmental biology
Subjects
Details
- ISSN :
- 00223751
- Volume :
- 593
- Database :
- OpenAIRE
- Journal :
- The Journal of Physiology
- Accession number :
- edsair.doi...........eb2bb6f009a68672bf8f6c9804e3324c