Abstract
Ca release from cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) is regulated by dyadic cleft [Ca] and intra-SR free [Ca] ([Ca]SR). Robust SR Ca release termination is important for stable excitation-contraction coupling, and partial [Ca]SR depletion may contribute to release termination. Here, we investigated the regulation of SR Ca release termination of spontaneous local SR Ca release events (Ca sparks) by [Ca]SR, release flux, and intra-SR Ca diffusion. We simultaneously measured Ca sparks and Ca blinks (localized elementary [Ca]SR depletions) in permeabilized ventricular cardiomyocytes over a wide range of SR Ca loads and release fluxes. Sparks terminated via a [Ca]SR-dependent mechanism at a fixed [Ca]SR depletion threshold independent of the initial [Ca]SR and release flux. Ca blink recovery depended mainly on intra-SR Ca diffusion rather than SR Ca uptake. Therefore, the large variation in Ca 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 release and [Ca]SR refilling reached a balance, preventing [Ca]SR from depleting to the termination threshold. Prolonged release events eventually terminated at a steady [Ca]SR, indicative of a slower, [Ca]SR-independent termination mechanism. These results demonstrate that there is high variability in local SR connectivity but that SR Ca release terminates at a fixed [Ca]SR termination threshold. Thus, reliable SR Ca release termination depends on tight RyR regulation by [Ca]SR.
| Original language | English (US) |
|---|---|
| Journal | Circulation Research |
| Volume | 103 |
| Issue number | 8 |
| DOIs | |
| State | Published - Oct 10 2008 |
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Keywords
- -induced Ca2
- Ca2
- Heart
- Release
- Ryanodine receptor
- Sarcoplasmic reticulum
- Sparks
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Termination of cardiac Ca2+ sparks : Role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion. / Zima, Aleksey V.; Picht, Eckard; Bers, Donald M; Blatter, Lothar A.
In: Circulation Research, Vol. 103, No. 8, 10.10.2008.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Termination of cardiac Ca2+ sparks
T2 - Role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion
AU - Zima, Aleksey V.
AU - Picht, Eckard
AU - Bers, Donald M
AU - Blatter, Lothar A.
PY - 2008/10/10
Y1 - 2008/10/10
N2 - Ca release from cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) is regulated by dyadic cleft [Ca] and intra-SR free [Ca] ([Ca]SR). Robust SR Ca release termination is important for stable excitation-contraction coupling, and partial [Ca]SR depletion may contribute to release termination. Here, we investigated the regulation of SR Ca release termination of spontaneous local SR Ca release events (Ca sparks) by [Ca]SR, release flux, and intra-SR Ca diffusion. We simultaneously measured Ca sparks and Ca blinks (localized elementary [Ca]SR depletions) in permeabilized ventricular cardiomyocytes over a wide range of SR Ca loads and release fluxes. Sparks terminated via a [Ca]SR-dependent mechanism at a fixed [Ca]SR depletion threshold independent of the initial [Ca]SR and release flux. Ca blink recovery depended mainly on intra-SR Ca diffusion rather than SR Ca uptake. Therefore, the large variation in Ca 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 release and [Ca]SR refilling reached a balance, preventing [Ca]SR from depleting to the termination threshold. Prolonged release events eventually terminated at a steady [Ca]SR, indicative of a slower, [Ca]SR-independent termination mechanism. These results demonstrate that there is high variability in local SR connectivity but that SR Ca release terminates at a fixed [Ca]SR termination threshold. Thus, reliable SR Ca release termination depends on tight RyR regulation by [Ca]SR.
AB - Ca release from cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) is regulated by dyadic cleft [Ca] and intra-SR free [Ca] ([Ca]SR). Robust SR Ca release termination is important for stable excitation-contraction coupling, and partial [Ca]SR depletion may contribute to release termination. Here, we investigated the regulation of SR Ca release termination of spontaneous local SR Ca release events (Ca sparks) by [Ca]SR, release flux, and intra-SR Ca diffusion. We simultaneously measured Ca sparks and Ca blinks (localized elementary [Ca]SR depletions) in permeabilized ventricular cardiomyocytes over a wide range of SR Ca loads and release fluxes. Sparks terminated via a [Ca]SR-dependent mechanism at a fixed [Ca]SR depletion threshold independent of the initial [Ca]SR and release flux. Ca blink recovery depended mainly on intra-SR Ca diffusion rather than SR Ca uptake. Therefore, the large variation in Ca 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 release and [Ca]SR refilling reached a balance, preventing [Ca]SR from depleting to the termination threshold. Prolonged release events eventually terminated at a steady [Ca]SR, indicative of a slower, [Ca]SR-independent termination mechanism. These results demonstrate that there is high variability in local SR connectivity but that SR Ca release terminates at a fixed [Ca]SR termination threshold. Thus, reliable SR Ca release termination depends on tight RyR regulation by [Ca]SR.
KW - -induced Ca2
KW - Ca2
KW - Heart
KW - Release
KW - Ryanodine receptor
KW - Sarcoplasmic reticulum
KW - Sparks
UR - http://www.scopus.com/inward/record.url?scp=54449087197&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=54449087197&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.107.183236
DO - 10.1161/CIRCRESAHA.107.183236
M3 - Article
C2 - 18787194
AN - SCOPUS:54449087197
VL - 103
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 8
ER -