Contractile activation in striated muscles requires a Ca 2+ reservoir of large capacity inside the sarcoplasmic reticulum (SR), presumably the protein calsequestrin. The buffering power of calsequestrin in vitro has a paradoxical dependence on Ca 2+ that should be valuable for function. Here, we demonstrate that this dependence is present in living cells. Ca 2+ signals elicited by membrane depolarization under voltage clamp were compared in single skeletal fibers of wild-type (WT) and double (d) Casq-null mice, which lack both calsequestrin isoforms. In nulls, Ca 2+ release started normally, but the store depleted much more rapidly than in the WT. This deficit was reflected in the evolution of SR evacuability, E , which is directly proportional to SR Ca 2+ permeability and inversely to its Ca 2+ buffering power, B . In WT mice E starts low and increases progressively as the SR is depleted. In dCasq-nulls, E started high and decreased upon Ca 2+ depletion. An elevated E in nulls is consistent with the decrease in B expected upon deletion of calsequestrin. The different value and time course of E in cells without calsequestrin indicate that the normal evolution of E reflects loss of B upon SR Ca 2+ depletion. Decrement of B upon SR depletion was supported further. When SR calcium was reduced by exposure to low extracellular Ca 2+ , release kinetics in the WT became similar to that in the dCasq-null. E became much higher, similar to that of null cells. These results indicate that calsequestrin not only stores Ca 2+ , but also varies its affinity in ways that progressively increase the ability of the store to deliver Ca 2+ as it becomes depleted, a novel feedback mechanism of potentially valuable functional implications. The study revealed a surprisingly modest loss of Ca 2+ storage capacity in null cells, which may reflect concurrent changes, rather than detract from the physiological importance of calsequestrin. Footnotes Abbreviations used in this paper: FDB flexor digitorum brevis NFRC normalized flux rate of change WT wild type Submitted: 16 April 2010 Accepted: 22 July 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
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Paradoxical buffering of calcium by calsequestrin demonstrated for the calcium store of skeletal muscle
Royer, Leandro; Sztretye, Monika; Manno, Carlo; Pouvreau, Sandrine; Zhou, Jingsong; Knollmann, Bjorn C.; Protasi, Feliciano; Allen, Paul D.; Ríos, Eduardo
Follow The Journal of General Physiology
, Volume 136 (3): 325
Rockefeller University Press – Sep 1, 2010
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