Ca2+ influx through CRAC channels activates cytosolic phospholipase A2, leukotriene C4 secretion, and expression of c-fos through ERK-dependent and -independent pathways in mast cells.

Wei Chiao Chang, Charmaine Nelson, Anant B. Parekh

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Cytosolic phospholipase A2 (cPLA2) 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 C4 (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 cPLA2. Ca2+ entry activates ERK indirectly, via recruitment of Ca2+-dependent protein kinase C alpha and betaI. 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 (cPLA2 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.

Original languageEnglish
Pages (from-to)2381-2383
Number of pages3
JournalFASEB Journal
Volume20
Issue number13
DOIs
Publication statusPublished - Nov 2006
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Ca2+ influx through CRAC channels activates cytosolic phospholipase A2, leukotriene C4 secretion, and expression of c-fos through ERK-dependent and -independent pathways in mast cells.'. Together they form a unique fingerprint.

  • Cite this