Contraction of cardiac myocytes is governed by calcium-ion (Ca2+)-induced Ca2+ release (CICR) from the sarcoplasmic reticulum through Ca2+-release channels. Ca2+ release occurs by concerted activation of numerous elementary Ca2+ events, ‘Ca2+ sparks’, that are triggered and locally controlled by Ca2+ influx into the cell through plasmalemmal L-type Ca2+ channels. Because of the positive feedback inherent in CICR, an as-yet-unidentified control mechanism is required to restrain the amplification of Ca2+ signalling and to terminate Ca2+ release from the sarcoplasmic reticulum. Here we use ultraviolet-laser-flash and two-photon photolysis of caged Ca2+ to study spatiotemporal features of the termination and refractoriness of Ca2+ release. Coherent and simultaneous activation of all Ca2+-release sites within a cardiac myocyte unmasked a prominent refractoriness, recovering monotonically within about 1 second. In contrast, selective activation of a few Ca2+-release sites was not followed by a refractoriness of Ca2+ release from the sarcoplasmic reticulum. This discrepancy is consistent with the idea that a functional depletion of Ca2+ from the cellular sarcoplasmic-reticulum network may underlie the refractoriness of CICR observed after a whole-cell Ca2+ transient. These results also imply the requirement for further mechanisms to terminate spatially limited subcellular Ca2+-release events such as Ca2+ sparks.
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This project was supported by the Swiss National Science Foundation, the Ciba Foundation and the Sandoz Foundation. We thank H.-R. Lüscher, S. Rohr and B. Schwaller for comments on the manuscript.
Correspondence and requests for materials should be addressed to E.N.
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DelPrincipe, F., Egger, M. & Niggli, E. Calcium signalling in cardiac muscle: refractoriness revealed by coherent activation. Nat Cell Biol 1, 323–329 (1999). https://doi.org/10.1038/14013
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