title: Dual action of neurokinin-1 antagonists on Mas-related GPCRs.
abstract: The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists.
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, and.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Azimi
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, and.
authors.forename: Vemuri B
authors.initials: VB
authors.lastname: Reddy
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Kai-Ting C
authors.initials: KC
authors.lastname: Shade
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Anthony
authors.affiliation: FM Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Talbot
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, and.|Programa de Pós-graduação em Biologia Celular e Molecular, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Paula Juliana Seadi
authors.initials: PJS
authors.lastname: Pereira
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, and.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Lerner
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008407:Mast Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D011537:Pruritus; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013373:Substance P
chemical_list: C480039:MRGPRX2 protein, human; C000596389:Mrgprb2 protein, mouse; D009419:Nerve Tissue Proteins; D064729:Neurokinin-1 Receptor Antagonists; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013373:Substance P