Abstract
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.
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