Abstract
The local control theory of excitation-contraction (EC) coupling in
cardiac muscle asserts that L-type Ca$^2+$ current tightly controls
Ca$^2+$ release from the sarcoplasmic reticulum (SR) via local
interaction of closely apposed L-type Ca$^2+$ channels (LCCs)
and ryanodine receptors (RyRs). These local interactions give rise
to smoothly graded Ca$^2+$-induced Ca$^2+$ release (CICR),
which exhibits high gain. In this study we present a biophysically
detailed model of the normal canine ventricular myocyte that conforms
to local control theory. The model formulation incorporates details
of microscopic EC coupling properties in the form of Ca$^2+$
release units (CaRUs) in which individual sarcolemmal LCCs interact
in a stochastic manner with nearby RyRs in localized regions where
junctional SR membrane and transverse-tubular membrane are in close
proximity. The CaRUs are embedded within and interact with the
global systems of the myocyte describing ionic and membrane pump/exchanger
currents, SR Ca$^2+$ uptake, and time-varying cytosolic ion concentrations
to form a model of the cardiac action potential (AP). The model can
reproduce both the detailed properties of EC coupling, such as variable
gain and graded SR Ca$^2+$ release, and whole-cell phenomena,
such as modulation of AP duration by SR Ca$^2+$ release. Simulations
indicate that the local control paradigm predicts stable APs when
the L-type Ca$^2+$ current is adjusted in accord with the balance
between voltage- and Ca$^2+$-dependent inactivation processes
as measured experimentally, a scenario where common pool models become
unstable. The local control myocyte model provides a means for studying
the interrelationship between microscopic and macroscopic behaviors
in a manner that would not be possible in experiments.
- acid
- action
- adaptor
- adrenergic,
- algorithms,
- amino
- amp-dependent
- animals,
- biological,
- biophysics,
- calcium
- calcium,
- cardiac,
- cardiovascular,
- cell
- cells,
- chains,
- channel
- channel,
- channels,
- comparative
- complexes,
- computer
- conduction
- contraction,
- cyclic
- dependent
- dogs,
- electrophysiology,
- expression
- extramural,
- gating,
- gene
- gov't,
- guinea
- heart
- humans,
- interaction
- ion
- ions,
- isoproterenol,
- kinase,
- kinases,
- l-type,
- long
- mapping,
- markov
- membrane
- membrane,
- models,
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