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J. Biol. Chem., Vol. 283, Issue 8, 4622-4631, February 22, 2008

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Local Ca²⁺ Influx through Ca²⁺ Release-activated Ca²⁺ (CRAC) Channels Stimulates Production of an Intracellular Messenger and an Intercellular Pro-inflammatory Signal^*

From the Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom

Ca²⁺ entry through store-operated Ca²⁺ channels drives the production of the pro-inflammatory molecule leukotriene C₄ (LTC₄) from mast cells through a pathway involving Ca²⁺-dependent protein kinase C, mitogen-activated protein kinases ERK1/2, phospholipase A₂, and 5-lipoxygenase. Here we examine whether local Ca²⁺ influx through store-operated Ca²⁺ release-activated Ca²⁺ (CRAC) channels in the plasma membrane stimulates this signaling pathway. Manipulating the amplitude and spatial extent of Ca²⁺ entry by altering chemical and electrical gradients for Ca²⁺ influx or changing the Ca²⁺ buffering of the cytoplasm all impacted on protein kinase C and ERK activation, generation of arachidonic acid and LTC₄ secretion, with little change in the bulk cytoplasmic Ca²⁺ rise. Similar bulk cytoplasmic Ca²⁺ concentrations were achieved when CRAC channels were activated in 0.25 mM external Ca²⁺ versus 2 mM Ca²⁺ and 100 nM La³⁺, an inhibitor of CRAC channels. However, despite similar bulk cytoplasmic Ca²⁺, protein kinase C activation and LTC₄ secretion were larger in 2 mM Ca²⁺ and La³⁺ than in 0.25 mM Ca²⁺, consistent with the central involvement of a subplasmalemmal Ca²⁺ rise. The nonreceptor tyrosine kinase Syk coupled CRAC channel opening to protein kinase C and ERK activation. Recombinant TRPC3 channels also activated protein kinase C, suggesting that subplasmalemmal Ca²⁺ rather than a microdomain exclusive to CRAC channels is the trigger. Hence a subplasmalemmal Ca²⁺ increase in mast cells is highly versatile in that it triggers cytoplasmic responses through generation of intracellular messengers as well as long distance changes through increased secretion of paracrine signals.

Received for publication, June 18, 2007 , and in revised form, December 20, 2007.

^* This work was supported by a Medical Research Council Program grant (to A. B. P.), Overseas Research Studentship, Y. Tan awards (to W.-C. C.), and a Christopher Welch scholarship (to J. D. C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 44-1865-272439; E-mail: anant.parekh{at}dpag.ox.ac.uk.

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