title: Activated N-formyl peptide receptor and high-affinity IgE receptor occupy common domains for signaling and internalization.
abstract: Immune cells display multiple cell surface receptors that integrate signals for survival, proliferation, migration, and degranulation. Here, immunogold labeling is used to map the plasma membrane distributions of two separate receptors, the N-formyl peptide receptor (FPR) and the high-affinity IgE receptor (FepsilonRI). We show that the FPR forms signaling clusters in response to monovalent ligand. These domains recruit Gi, followed by the negative regulatory molecule arrestin2. There are low levels of colocalization of FPR with FcepsilonRI in unstimulated cells, shown by computer simulation to be a consequence of receptor density. Remarkably, there is a large increase in receptor coclustering when cells are simultaneously treated with N-formyl-methionyl-leucyl-phenylalanine and IgE plus polyvalent antigen. The proximity of two active receptors may promote localized cross-talk, leading to enhanced inositol-(3,4,5)-trisphosphate production and secretion. Some cointernalization and trafficking of the two receptors can be detected by live cell imaging, but the bulk of FPR and FcepsilonRI segregates over time. This segregation is associated with more efficient internalization of cross-linked FcepsilonRI than of arrestin-desensitized FPR. The observation of receptors in lightly coated membrane invaginations suggests that, despite the lack of caveolin, hematopoietic cells harbor caveolae-like structures that are candidates for nonclathrin-mediated endocytosis.
authors.affiliation: Department of Pathology and Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xue
authors.forename: Genie
authors.initials: G
authors.lastname: Hsieh
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Raymond-Stintz
authors.forename: Janet
authors.initials: J
authors.lastname: Pfeiffer
authors.forename: Diana
authors.initials: D
authors.lastname: Roberts
authors.forename: Stanly L
authors.initials: SL
authors.lastname: Steinberg
authors.forename: Janet M
authors.initials: JM
authors.lastname: Oliver
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
authors.forename: Diane S
authors.initials: DS
authors.lastname: Lidke
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Wilson
mesh_terms: D019393:Arrestin / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006098:Granulocytes; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D044042:Receptors, Formyl Peptide / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D019393:Arrestin; D007295:Inositol Phosphates; D044042:Receptors, Formyl Peptide; D017455:Receptors, IgE; C118500:inositol 3,4,5-trisphosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go