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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1805    most recent 01160.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Gudzenko, V. Articles by Olcese, R. Search for Related Content PubMed PubMed Citation Articles by Gudzenko, V. Articles by Olcese, R.

Influence of channel subunit composition on L-type Ca²⁺ current kinetics and cardiac wave stability

¹Department of Anesthesiology, Division of Molecular Medicine, ²Department of Medicine, Division of Cardiology, and ³Cardiovascular Research Laboratory, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles; ⁴Department of Physics, California State University Northridge, Northridge, California

Submitted 22 October 2006 ; accepted in final form 29 May 2007

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 Ca²⁺ 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 Ca²⁺ channel (Ca_v1.2) coexpressed with the ₂-subunit alone (_1C + ₂) or in combination with _2a, _2b, or ₃ subunits (_1C + ₂ + ), using Ca²⁺ as the charge carrier. We then incorporated the kinetic properties observed experimentally into the L-type Ca²⁺ 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 Ca²⁺ channel. Assuming that _2b most closely resembles the native cardiac L-type Ca²⁺ current, the absence of , as well as the coexpression of _2a, was found to flatten restitution slope and stabilize spiral waves. These results imply that subunit modification of L-type Ca²⁺ channels can potentially be used as an antifibrillatory strategy.

Ca²⁺ channel; restitution; cardiac action potential; spiral waves; beta subunit