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All-or-None Activation of CRAC Channels by Agonist Elicits Graded Responses in Populations of Mast Cells¹

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

In nonexcitable cells, receptor stimulation evokes Ca²⁺ release from the endoplasmic reticulum stores followed by Ca²⁺ influx through store-operated Ca²⁺ channels in the plasma membrane. In mast cells, store-operated entry is mediated via Ca²⁺ release-activated Ca²⁺ (CRAC) channels. In this study, we find that stimulation of muscarinic receptors in cultured mast cells results in Ca²⁺-dependent activation of protein kinase C and the mitogen activated protein kinases ERK1/2 and this is required for the subsequent stimulation of the enzymes Ca²⁺-dependent phospholipase A₂ and 5-lipoxygenase, generating the intracellular messenger arachidonic acid and the proinflammatory intercellular messenger leukotriene C₄. In cell population studies, ERK activation, arachidonic acid release, and leukotriene C₄ secretion were all graded with stimulus intensity. However, at a single cell level, Ca²⁺ influx was related to agonist concentration in an essentially all-or-none manner. This paradox of all-or-none CRAC channel activation in single cells with graded responses in cell populations was resolved by the finding that increasing agonist concentration recruited more mast cells but each cell responded by generating all-or-none Ca²⁺ influx. These findings were extended to acutely isolated rat peritoneal mast cells where muscarinic or P2Y receptor stimulation evoked all-or-none activation of Ca²⁺entry but graded responses in cell populations. Our results identify a novel way for grading responses to agonists in immune cells and highlight the importance of CRAC channels as a key pharmacological target to control mast cell activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an Medical Research Council Programme Grant (to A.B.P.). W.-C.C. was a recipient of an Overseas Research Studentship award and J.D.C. held a Christopher Welch Scholarship.

² Address correspondence and reprint requests to Prof. Anant Parekh, Oxford University, Parks Road, Oxford, U.K. E-mail address: anant.parekh{at}dpag.ox.ac.uk

³ Abbreviations used in this paper: CRAC, Ca²⁺ release-activated Ca²⁺; cPLA₂, Ca²⁺-dependent phospholipase A₂; LTC₄, leukotriene C₄; InsP₃, inositol 1,4,5-trisphosphate; 2-APB, 2-aminoethyldiphenyl borate.

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