Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical model

Thomas R. Shannon, Fei Wang, Donald M Bers

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Cardiac excitation-contraction coupling is initialized by the release of Ca from the sarcoplasmic reticulum (SR) in response to a sudden increase in local cytosolic [Ca] ([Ca]i) within the junctional cleft. We have tested the hypothesis that functional ryanodine receptor (RyR) regulation plays a major role in the regulation of myocyte Ca. A mathematical model with unique characteristics was used to simulate Ca homeostasis. Specifically, the model was designed to accurately represent the SR [Ca]-dependence of release from a variety of experimentally produced data sets. The simulated data for altered RyR Ca sensitivity demonstrated a regulatory feedback loop that resulted in the same release at lower [Ca]SR. This suggests that the primary role of myocyte RyR regulation may be to decrease SR [Ca] without decreasing the size of the [Ca]i transient. The model results suggest that this action moderates the increased SR [Ca] observed with adrenergic stimulation and may keep the [Ca]SR below the threshold for delayed afterdepolarizations and arrhythmia. However, increased Ca affinity of the RyR increased the probability of delayed afterdepolarizations when heart failure was simulated. We conclude that RyR regulation may play a role in preventing arrhythmias in healthy myocytes but that the same regulation may have the opposite effect in chronic heart failure.

Original languageEnglish (US)
Pages (from-to)4096-4110
Number of pages15
JournalBiophysical Journal
Volume89
Issue number6
DOIs
StatePublished - Dec 2005
Externally publishedYes

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Sarcoplasmic Reticulum
Ryanodine Receptor Calcium Release Channel
Theoretical Models
Muscle Cells
Cardiac Arrhythmias
Heart Failure
Excitation Contraction Coupling
Adrenergic Agents
Homeostasis

ASJC Scopus subject areas

  • Biophysics

Cite this

Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical model. / Shannon, Thomas R.; Wang, Fei; Bers, Donald M.

In: Biophysical Journal, Vol. 89, No. 6, 12.2005, p. 4096-4110.

Research output: Contribution to journalArticle

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