title: E-selectin permits communication between PAF receptors and TRPC channels in human neutrophils.
abstract: The selectin family of molecules (L-, P-, and E-selectin) mediates adhesive interactions between leukocytes and endothelial cells required for recruitment of leukocytes to inflammatory sites. Soluble E-selectin levels are elevated in inflammatory diseases and act to promote neutrophil beta(2)-integrin-mediated adhesion by prolonging Ca(2+) mobilization. Although soluble E-selectin alone was unable to initiate Ca(2+) signaling, it allowed a novel "permissive" store-operative calcium entry (SOCE) following the initial platelet-activating factor (PAF)-induced release of Ca(2+) from inositol 1,4,5-trisphosphate (IP(3))-sensitive stores. This induction of permissive SOCE in response to soluble E-selectin and PAF was shown to act through a G protein-coupled receptor (GPCR) coupled to pertussis toxin-insensitive G(q/11). Furthermore, we demonstrated that permissive SOCE was mediated by canonical transient receptor potential channel (TRPC) due to its sensitivity to specific inhibition by MRS1845 and Gd(3+) and that TRPC6 was the principal TRPC family member expressed by human neutrophils. In terms of mechanism, we demonstrated that soluble E-selectin activated Src family tyrosine kinases, an effect that was upstream of phosphatidylinositol 3'-kinase in a signaling pathway that regulates permissive SOCE following exposure of neutrophils to PAF. In summary, this report provides the first evidence for communication between an inflammatory mediator and adhesion receptors at a molecular level, through selectin receptor ligation allowing permissive SOCE to occur following PAF stimulation of human neutrophils.
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: McMeekin
authors.forename: Ian
authors.initials: I
authors.lastname: Dransfield
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.forename: Christopher
authors.initials: C
authors.lastname: Haslett
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Walker
mesh_terms: D018821:CD18 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D019040:E-Selectin / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D009568:Nitrendipine / Q000031:analogs & derivatives / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000378:metabolism / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011940:Receptor Aggregation / Q000187:drug effects / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D019040:E-Selectin; C503978:MRS 1845; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; C039351:platelet activating factor receptor; D015544:Inositol 1,4,5-Trisphosphate; D009568:Nitrendipine; D019061:src-Family Kinases; D002118:Calcium