Abstract
Activation of the beta-adrenergic (beta-AR) signaling pathway enhances
cardiac function through protein kinase A (PKA)-mediated phosphorylation
of target proteins involved in the process of excitation-contraction
(EC) coupling. Experimental studies of the effects of beta-AR stimulation
on EC coupling have yielded complex results, including increased,
decreased, or unchanged EC coupling gain. In this study, we extend
a previously developed model of the canine ventricular myocyte describing
local control of sarcoplasmic reticulum (SR) calcium (Ca$^2+$)
release to include the effects of beta-AR stimulation. Incorporation
of phosphorylation-dependent effects on model membrane currents and
Ca$^2+$-cycling proteins yields changes of action potential (AP)
and Ca$^2+$ transients in agreement with those measured experimentally
in response to the nonspecific beta-AR agonist isoproterenol (ISO).
The model reproduces experimentally observed alterations in EC coupling
gain in response to beta-AR agonists and predicts the specific roles
of L-type Ca$^2+$ channel (LCC) and SR Ca$^2+$ release channel
phosphorylation in altering the amplitude and shape of the EC coupling
gain function. The model also indicates that factors that promote
mode 2 gating of LCCs, such as beta-AR stimulation or activation
of the Ca$^2+$/calmodulin-dependent protein kinase II (CaMKII),
may increase the probability of occurrence of early after-depolarizations
(EADs), due to the random, long-duration opening of LCC gating in
mode 2.
- acid
- action
- adaptor
- adrenergic,
- algorithms,
- amino
- amp-dependent
- animals,
- beta,
- biological,
- biophysics,
- calcium
- calcium,
- cardiac,
- cardiovascular,
- cell
- cells,
- chains,
- channel
- channel,
- channels,
- comparative
- complexes,
- computer
- conduction
- contraction,
- cyclic
- dependent
- dogs,
- electrophysiology,
- expression
- extramural,
- factors,
- gating,
- gene
- gov't,
- guinea
- heart
- humans,
- interaction
- ion
- ions,
- isoproterenol,
- kinase,
- kinases,
- l-type,
- long
- mapping,
- markov
- membrane
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