Kinetic properties of the cardiac L-type Ca2+ channel and its role in myocyte electrophysiology: a theoretical investigation

The L-type Ca(2+) channel (Ca(V)1.2) 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(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(2+)-dependent inactivation (CDI) to total inactivation of Ca(V)1.2; and 3), description of dynamic Ca(V)1.2 and ryanodine receptor channel-state occupancy during the AP. Results are: 1), the Ca(V)1.2 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(V)1.2 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(V)1.2 dominance. 4), The relative contribution of CDI to total inactivation of Ca(V)1.2 is greater at negative potentials, when VDI is weak; and 5), loss of VDI due to the Ca(V)1.2 mutation G406R (linked to the Timothy syndrome) results in APD prolongation and increased CaT.