Non-equilibrium Gating in cardiac Na+ channels - An original mechanism of arrhythmia

Article

关键词: LONG-QT SYNDROME;    LIFE-THREATENING ARRHYTHMIAS;    MUTATIONS;    CHANNELOPATHIES;    INACTIVATION;    PHENOTYPE;    MYOTONIA;    EPILEPSY;    DISEASE;   

DOI  :  10.1161/01.CIR.0000069273.51375.BD

来源: SCIE

【 摘 要 】

Background - Many long-QT syndrome (LQTS) mutations in the cardiac Na+ channel result in a gain of function due to a fraction of channels that fail to inactivate ( burst), leading to sustained current (I-sus) during depolarization. However, some Na+ channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase I-sus (<0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype. Methods and Results - We developed new experimental approaches based on theoretical analyses to investigate Na+ channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation. Conclusions - Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.

【 授权许可】

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