Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions

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Journal titleNature
Pages237241; # of pages: 5
Subjectatracurium besilate; beta n acetylhexosaminidase; cetrorelix; ciprofloxacin; compound 48-80; G protein coupled receptor; histamine; icatibant; immunoglobulin E antibody; insulin; leuprorelin; octreotide; prostaglandin D2; quinolone derivative; sermorelin; tumor necrosis factor; anaphylaxis; animal experiment; animal model; artificial ventilation; cell activation; cell survival; drug hypersensitivity; HEK293 cell line; histamine release; human; human cell; in vitro study; in vivo study; injection site inflammation; mouse; peritoneum mast cell; reverse transcription polymerase chain reaction; structure activity relation
AbstractMast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.
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AffiliationNational Research Council Canada (NRC-CNRC); National Institute for Nanotechnology
Peer reviewedYes
NPARC number21275741
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Record identifierfb39852b-fab2-4219-9867-64331bd6c08c
Record created2015-07-14
Record modified2016-05-09
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