title: Store-Operated Ca2+ Release-Activated Ca2+ Channels Regulate PAR2-Activated Ca2+ Signaling and Cytokine Production in Airway Epithelial Cells.
abstract: The G-protein-coupled protease-activated receptor 2 (PAR2) plays an important role in the pathogenesis of various inflammatory and auto-immune disorders. In airway epithelial cells (AECs), stimulation of PAR2 by allergens and proteases triggers the release of a host of inflammatory mediators to regulate bronchomotor tone and immune cell recruitment. Activation of PAR2 turns on several cell signaling pathways of which the mobilization of cytosolic Ca(2+) is likely a critical but poorly understood event. In this study, we show that Ca(2+) release-activated Ca(2+) (CRAC) channels encoded by stromal interaction molecule 1 and Orai1 are a major route of Ca(2+) entry in primary human AECs and drive the Ca(2+) elevations seen in response to PAR2 activation. Activation of CRAC channels induces the production of several key inflammatory mediators from AECs including thymic stromal lymphopoietin, IL-6, and PGE2, in part through stimulation of gene expression via nuclear factor of activated T cells (NFAT). Furthermore, PAR2 stimulation induces the production of many key inflammatory mediators including PGE2, IL-6, IL-8, and GM-CSF in a CRAC channel-dependent manner. These findings indicate that CRAC channels are the primary mechanism for Ca(2+) influx in AECs and a vital checkpoint for the induction of PAR2-induced proinflammatory cytokines.
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Amit
authors.initials: A
authors.lastname: Jairaman
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Division of Allergy/Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schleimer
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and m-prakriya@northwestern.edu.
authors.forename: Murali
authors.initials: M
authors.lastname: Prakriya
mesh_terms: D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D034622:RNA Interference; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D014357:Trypsin / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D009842:Oligopeptides; D044464:Receptor, PAR-2; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; C445503:transcription factor NF-AT c3; D014357:Trypsin; D002118:Calcium