Journal
FASEB JOURNAL
Volume 20, Issue 13, Pages 2381-+Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.06-6016fje
Keywords
store-operated influx; 5-lipoxygenase; protein kinase
Categories
Funding
- MRC [G0200218] Funding Source: UKRI
- Medical Research Council [G0200218] Funding Source: researchfish
- Medical Research Council [G0200218] Funding Source: Medline
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Cytosolic phospholipase A(2) (cPLA(2)) is a Ca2+-dependent enzyme that mediates agonist-dependent arachidonic acid release in most cell types. Arachidonic acid can then be metabolized by the 5-lipoxygenase enzyme to generate the proinflammatory signal leukotriene C-4 (LTC4). Here we report that Ca2+ entry through store-operated CRAC (Ca2+ release-activated Ca2+) channels activates the extracellular signal-regulated kinases (ERKs), members of the mitogen-activated protein kinase family, within minutes and this is necessary for stimulation of cPLA(2). Ca2+ entry activates ERK indirectly, via recruitment of Ca2+-dependent protein kinase C alpha and beta I. Ca2+ influx also promotes translocation of cytosolic 5-lipoxygenase to the nuclear membrane, a key step in the activation of this enzyme. Translocation is dependent on ERK activation. A role for gene activation is shown by the finding that CRAC channel opening results in increased transcription and translation of c-fos. Inhibition of ERK activation failed to prevent c-fos expression. Our results show that CRAC channel activation elicits short-term effects through the co-coordinated regulation of two metabolic pathways (cPLA(2) and 5-lipoxygenase), which results in the generation of both intra- and intercellular messengers within minutes, as well as longer term changes involving gene activation. These short-term effects are mediated via ERK, whereas, paradoxically, c-fos expression is not. Ca2+ influx through CRAC channels can therefore activate different signaling pathways at the same time, culminating in a range of temporally diverse responses.
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