Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: A computational analysis.
BACKGROUND
D1790G, a mutation of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, is linked to 1 form of the congenital long-QT syndrome (LQT-3). In contrast to other LQT-3-linked SCN5A mutations, D1790G does not promote sustained Na(+) channel activity but instead alters the kinetics and voltage-dependence of the inactivated state.


RESULTS
We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na(+) channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na(+) channel activity prolong APs in a steeply heart rate-dependent manner not directly due to changes in Na(+) entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents.


CONCLUSIONS
We conclude that the D1790G mutation of the Na(+) channel alpha-subunit can prolong the cardiac ventricular AP despite the absence of mutation-induced sustained Na(+) channel current. This prolongation is calcium-dependent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early afterdepolarizations.
Wehrens
X H
XH
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Abriel
H
H
Cabo
C
C
Benhorin
J
J
Kass
R S
RS
D000200:Action Potentials; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D006339:Heart Rate; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D011994:Recombinant Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D016276:Ventricular Function / Q000502:physiology*
D062554:NAV1.5 Voltage-Gated Sodium Channel; D011994:Recombinant Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D002118:Calcium