Influence of channel subunit composition on L-type Ca2+ current kinetics and cardiac wave stability.
Previous studies have demonstrated that the slope of the function relating the action potential duration (APD) and the diastolic interval, known as the APD restitution curve, plays an important role in the initiation and maintenance of ventricular fibrillation. Since the APD restitution slope critically depends on the kinetics of the L-type Ca(2+) current, we hypothesized that manipulation of the subunit composition of these channels may represent a powerful strategy to control cardiac arrhythmias. We studied the kinetic properties of the human L-type Ca(2+) channel (Ca(v)1.2) coexpressed with the alpha(2)delta-subunit alone (alpha(1C) + alpha(2)delta) or in combination with beta(2a), beta(2b), or beta(3) subunits (alpha(1C) + alpha(2)delta + beta), using Ca(2+) as the charge carrier. We then incorporated the kinetic properties observed experimentally into the L-type Ca(2+) current mathematical model of the cardiac action potential to demonstrate that the APD restitution slope can be selectively controlled by altering the subunit composition of the Ca(2+) channel. Assuming that beta(2b) most closely resembles the native cardiac L-type Ca(2+) current, the absence of beta, as well as the coexpression of beta(2a), was found to flatten restitution slope and stabilize spiral waves. These results imply that subunit modification of L-type Ca(2+) channels can potentially be used as an antifibrillatory strategy.
Gudzenko
Vadim
V
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California Los Angeles 90095-7115, USA.
Shiferaw
Yohannes
Y
Savalli
Nicoletta
N
Vyas
Roshni
R
Weiss
James N
JN
Olcese
Riccardo
R
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014693:Ventricular Fibrillation / Q000503:physiopathology; D014982:Xenopus laevis
D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D021122:Protein Subunits