Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia.
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 (Isus) 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 Isus (<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.


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.
Clancy
Colleen E
CE
Department of Pharmacology, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA.
Tateyama
Michihiro
M
Liu
Huajun
H
Wehrens
Xander H T
XH
Kass
Robert S
RS
D000200:Action Potentials; D002460:Cell Line; D019295:Computational Biology; D003198:Computer Simulation; D004553:Electric Conductivity; D006321:Heart / Q000503:physiopathology; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000209:etiology*; D008955:Models, Cardiovascular; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels