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Kinetic Properties of the Cardiac L-Type Ca²⁺ Channel and Its Role in Myocyte Electrophysiology: A Theoretical Investigation

Gregory M. Faber ^*, Jonathan Silva , Leonid Livshitz  and Yoram Rudy 

^* Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio; and Cardiac Bioelectricity and Arrhythmia Center and Department of Biomedical Engineering, Washington University, St. Louis, Missouri

Correspondence: Address reprint requests to Yoram Rudy, Director, Cardiac Bioelectricity and Arrhythmia Center, 290 Whitaker Hall, Campus Box 1097, One Brookings Dr., St. Louis, MO 63130-4899. Tel.: 314-935-8160; Fax: 314-935-8168; E-mail: rudy{at}wustl.edu.

The L-type Ca²⁺ channel (Ca_V1.2) plays an important role in action potential (AP) generation, morphology, and duration (APD) and is the primary source of triggering Ca²⁺ for the initiation of Ca²⁺-induced Ca²⁺-release in cardiac myocytes. In this article we present: 1), a detailed kinetic model of Ca_V1.2, which is incorporated into a model of the ventricular mycoyte where it interacts with a kinetic model of the ryanodine receptor in a restricted subcellular space; 2), evaluation of the contribution of voltage-dependent inactivation (VDI) and Ca²⁺-dependent inactivation (CDI) to total inactivation of Ca_V1.2; and 3), description of dynamic Ca_V1.2 and ryanodine receptor channel-state occupancy during the AP. Results are: 1), the Ca_V1.2 model reproduces experimental single-channel and macroscopic-current data; 2), the model reproduces rate dependence of APD, [Na⁺]_i, and the Ca²⁺-transient (CaT), and restitution of APD and CaT during premature stimuli; 3), CDI of Ca_V1.2 is sensitive to Ca²⁺ that enters the subspace through the channel and from SR release. The relative contributions of these Ca²⁺ sources to total CDI during the AP vary with time after depolarization, switching from early SR dominance to late Ca_V1.2 dominance. 4), The relative contribution of CDI to total inactivation of Ca_V1.2 is greater at negative potentials, when VDI is weak; and 5), loss of VDI due to the Ca_V1.2 mutation G406R (linked to the Timothy syndrome) results in APD prolongation and increased CaT.

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