Kinetic Properties of the Cardiac L-Type Ca^sup 2+^ Channel and Its Role in Myocyte Electrophysiology: A Theoretical Investigation

The L-type Ca^sup 2+^ channel (Ca^sub v^1.2) plays an important role in action potential (AP) generation, morphology, and duration (APD) and is the primary source of triggering Ca^sup 2+^ for the initiation of Ca^sup 2+^-induced Ca^sup 2+^-release in cardiac myocytes. In this article we present: 1), a detailed kinetic model of Ca^sub v^1.2, 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 Ca^sup 2+^-dependent inactivation (CDI) to total inactivation of Ca^sub v^1.2; and 3), description of dynamic Ca^sub v^1.2 and ryanodine receptor channel-state occupancy during the AP. Results are: 1), the Ca^sub v^1.2 model reproduces experimental single-channel and macroscopic-current data; 2), the model reproduces rate dependence of APD, [Na+]^sub i^, and the Ca^sup 2+^-transient (CaT), and restitution of APD and CaT during premature stimuli; 3), CDI of Ca^sub v^1.2 is sensitive to Ca^sup 2+^ that enters the subspace through the channel and from SR release. The relative contributions of these Ca^sup 2+^ sources to total CDI during the AP vary with time after depolarization, switching from early SR dominance to late Ca^sub v^1.2 dominance. 4), The relative contribution of CDI to total inactivation of Ca^sub v^1.2 is greater at negative potentials, when VDI is weak; and 5), loss of VDI due to the Ca^sub v^1.2 mutation G406R (linked to the Timothy syndrome) results in APD prolongation and increased CaT. [PUBLICATION ABSTRACT]