Regulation of Cardiac Sarcoplasmic Reticulum Ca Release by Luminal [Ca] and Altered Gating Assessed with a Mathematical Model

¹ Rush University Med. Ctr.
² Loyola University Med. Ctr.
³ Loyola University Med. Ctr.

^* To whom correspondence should be addressed. E-mail: tshannon{at}rush.edu.

Submitted on June 16, 2005
Revised on July 27, 2005
Accepted on 26 August 2005

	Abstract

Cardiac excitation-contraction coupling (ECC) is initialized by the release of Ca from the 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 which 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 after-depolarizations (DADs) and arrhythmia. However, increased Ca affinity of the RyR increased the probability of DADs 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.

Key Words: cardiac arrhythmias, excitation-contraction coupling, heart failure, mathematical modeling, ryanodine receptor, sarcoplasmic reticulum

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