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

The L-type Ca2+ channel (CaV1.2) 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 CaV1.2, 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 CaV1.2; and 3), description of dynamic CaV1.2 and ryanodine receptor channel-state occupancy during the AP. Results are: 1), the CaV1.2 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 CaV1.2 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 CaV1.2 dominance. 4), The relative contribution of CDI to total inactivation of CaV1.2 is greater at negative potentials, when VDI is weak; and 5), loss of VDI due to the CaV1.2 mutation G406R (linked to the Timothy syndrome) results in APD prolongation and increased CaT.