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Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells

Abstract

Ca2+-induced Ca2+ release is a general mechanism that most cells use to amplify Ca2+ signals1,2,3,4,5. In heart cells, this mechanism is operated between voltage-gated L-type Ca2+ channels (LCCs) in the plasma membrane and Ca2+ release channels, commonly known as ryanodine receptors, in the sarcoplasmic reticulum3,4,5. The Ca2+ influx through LCCs traverses a cleft of roughly 12 nm formed by the cell surface and the sarcoplasmic reticulum membrane, and activates adjacent ryanodine receptors to release Ca2+ in the form of Ca2+ sparks6. Here we determine the kinetics, fidelity and stoichiometry of coupling between LCCs and ryanodine receptors. We show that the local Ca2+ signal produced by a single opening of an LCC, named a ‘Ca2+ sparklet’, can trigger about 4–6 ryanodine receptors to generate a Ca2+ spark. The coupling between LCCs and ryanodine receptors is stochastic, as judged by the exponential distribution of the coupling latency. The fraction of sparklets that successfully triggers a spark is less than unity and declines in a use-dependent manner. This optical analysis of single-channel communication affords a powerful means for elucidating Ca2+-signalling mechanisms at the molecular level.

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Figure 1: Confocal visualization of single LCC Ca2+ transients, ‘Ca2+ sparklets’.
Figure 2: Quantitative relation between iCa and sparklets.
Figure 3: A Ca2+ spark triggered by single LCC opening.
Figure 4: Sparklet–spark coupling under loose patch-clamp conditions.
Figure 5: Visualization of the Ca2+ sparklets that immediately precede triggered Ca2+ sparks.
Figure 6: Latency and fidelity of LCC–RyR coupling.

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Acknowledgements

We thank W. J. Lederer, M. B. Cannell, M. D. Stern, E. Ríos, J. S. K. Sham, S. J. Sollott, I. Josephson and R. P. Xiao for critical comments on the manuscript; H. A. Spurgeon for technical support; and A. Erauth for secretarial assistance. This work was supported by the NIH intramural research program (to E.G.L. and H.C.) and grants from the National Natural Science Foundation of China (H.C.).

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Correspondence to Heping Cheng.

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Wang, SQ., Song, LS., Lakatta, E. et al. Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature 410, 592–596 (2001). https://doi.org/10.1038/35069083

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