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

¹ Case Western Reserve University
² Washington University in St. Louis

^* To whom correspondence should be addressed. E-mail: gmf4{at}case.edu.

Submitted on May 11, 2006
Revised on June 19, 2006
Accepted on 20 November 2006

	Abstract

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 (RyR) 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. 3.) Description of dynamic Ca_V1.2 and RyR channel-state occupancy during the AP. Results: 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. 5.) Loss of VDI due to the Ca_V1.2 mutation G406R (linked to the Timothy syndrome) results in APD prolongation and increased CaT.

Key Words: Ca_V1.2, action potential, calcium-induced calcium-release, electrophysiology, ion channels, ryanodine receptor

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