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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.

Original publication

DOI

10.1074/jbc.M705002200

Type

Journal article

Journal

J Biol Chem

Publication Date

22/02/2008

Volume

283

Pages

4622 - 4631

Keywords

Arachidonate 5-Lipoxygenase, Arachidonic Acid, Calcium, Calcium Channel Blockers, Calcium Signaling, Cell Line, Cytoplasm, Dose-Response Relationship, Drug, Enzyme Activation, Humans, Inflammation Mediators, Intracellular Signaling Peptides and Proteins, Lanthanum, Leukotriene C4, MAP Kinase Signaling System, Mast Cells, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Paracrine Communication, Phospholipases A2, Protein Kinase C, Protein-Tyrosine Kinases, Recombinant Proteins, Syk Kinase, TRPC Cation Channels