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Calcium signalling in cardiac muscle: refractoriness revealed by coherent activation


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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Figure 1: Properties of [Ca2+]i and Na+/Ca2+-exchange inward currents (INa/Ca).
Figure 2: Estimates of whole-cell [Ca2+]i with INa/Ca.
Figure 3: Confocal Ca2+ images of paired two-photon-photolytic Ca2+ signals.
Figure 4: Comparison of local and coherent whole-cell Ca2+ release.
Figure 5: Global Ca2+-release signals suppress subsequent local events but not vice versa.
Figure 6: Alternans of INa/Ca observed during trains of whole-cell laser flashes.


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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).

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