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

Abstract

The L-type Ca 2+ channel (Ca V1.2) plays an important role in action potential (AP) generation, morphology, and duration (APD) and is the primary source of triggering Ca 2+ for the initiation of Ca 2+-induced Ca 2+-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 Ca 2+-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 Ca 2+-transient (CaT), and restitution of APD and CaT during premature stimuli; 3), CDI of Ca V1.2 is sensitive to Ca 2+ that enters the subspace through the channel and from SR release. The relative contributions of these Ca 2+ 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.