Regulation of ryanodine receptor opening by lumenal Ca²⁺ underlies quantal Ca²⁺ release in PC12 cells

Koizumi, Schuichi; Lipp, Peter; Berridge, Michael J. and Bootman, Martin D. (1999). Regulation of ryanodine receptor opening by lumenal Ca²⁺ underlies quantal Ca²⁺ release in PC12 cells. Journal of Biological Chemistry, 274(47) pp. 33327–33333.

DOI: https://doi.org/10.1074/jbc.274.47.33327

URL: http://www.jbc.org/content/274/47/33327.full.pdf+h...

Abstract

Graded or "quantal" Ca²⁺ release from intracellular stores has been observed in various cell types following activation of either ryanodine receptors (RyR) or inositol 1,4,5-trisphosphate receptors (InsP₃R). The mechanism causing the release of Ca²⁺ stores in direct proportion to the strength of stimulation is unresolved. We investigated the properties of quantal Ca²⁺ release evoked by activation of RyR in PC12 cells, and in particular whether the sensitivity of RyR to the agonist caffeine was altered by lumenal Ca²⁺. Quantal Ca²⁺ release was observed in cells stimulated with 1 to 40 mM caffeine, a range of caffeine concentrations giving a >10-fold change in lumenal Ca²⁺ content. The Ca²⁺ load of the caffeine-sensitive stores was modulated by allowing them to refill for varying times after complete discharge with maximal caffeine, or by depolarizing the cells with K⁺ to enhance their normal steady-state loading. The threshold for RyR activation was sensitized approximately 10-fold as the Ca²⁺ load increased from a minimal to a maximal loading. In addition, the fraction of Ca²⁺ released by low caffeine concentrations increased. Our data suggest that RyR are sensitive to lumenal Ca²⁺ over the full range of Ca²⁺ loads that can be achieved in an intact PC12 cell, and that changes in RyR sensitivity may be responsible for the termination of Ca²⁺ release underlying the quantal effect.

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