Affiliation:
1. From the Department of Molecular Biophysics and Physiology (A.V.Z., L.A.B.), Rush University Medical Center, Chicago, Ill; and Department of Pharmacology (E.P., D.M.B.), University of California, Davis.
Abstract
Ca
2+
release from cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) is regulated by dyadic cleft [Ca
2+
] and intra-SR free [Ca
2+
] ([Ca
2+
]
SR
). Robust SR Ca
2+
release termination is important for stable excitation–contraction coupling, and partial [Ca
2+
]
SR
depletion may contribute to release termination. Here, we investigated the regulation of SR Ca
2+
release termination of spontaneous local SR Ca
2+
release events (Ca
2+
sparks) by [Ca
2+
]
SR
, release flux, and intra-SR Ca
2+
diffusion. We simultaneously measured Ca
2+
sparks and Ca
2+
blinks (localized elementary [Ca
2+
]
SR
depletions) in permeabilized ventricular cardiomyocytes over a wide range of SR Ca
2+
loads and release fluxes. Sparks terminated via a [Ca
2+
]
SR
-dependent mechanism at a fixed [Ca
2+
]
SR
depletion threshold independent of the initial [Ca
2+
]
SR
and release flux. Ca
2+
blink recovery depended mainly on intra-SR Ca
2+
diffusion rather than SR Ca
2+
uptake. Therefore, the large variation in Ca
2+
blink recovery rates at different release sites occurred because of differences in the degree of release site interconnection within the SR network. When SR release flux was greatly reduced, long-lasting release events occurred from well-connected junctions. These junctions could sustain release because local SR Ca
2+
release and [Ca
2+
]
SR
refilling reached a balance, preventing [Ca
2+
]
SR
from depleting to the termination threshold. Prolonged release events eventually terminated at a steady [Ca
2+
]
SR
, indicative of a slower, [Ca
2+
]
SR
-independent termination mechanism. These results demonstrate that there is high variability in local SR connectivity but that SR Ca
2+
release terminates at a fixed [Ca
2+
]
SR
termination threshold. Thus, reliable SR Ca
2+
release termination depends on tight RyR regulation by [Ca
2+
]
SR
.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
137 articles.
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