title: Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
abstract: The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side effect of this widely used antimalarial drug. Here, we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that MrgprA3 is required for CQ responsiveness in mice. Furthermore, MrgprA3-expressing neurons respond to histamine and coexpress gastrin-releasing peptide, a peptide involved in itch sensation, and MrgprC11. Activation of these neurons with the MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore, Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Zongxiang
authors.initials: Z
authors.lastname: Tang
authors.forename: Lenka
authors.initials: L
authors.lastname: Surdenikova
authors.forename: Seungil
authors.initials: S
authors.lastname: Kim
authors.forename: Kush N
authors.initials: KN
authors.lastname: Patel
authors.forename: Andrew
authors.initials: A
authors.lastname: Kim
authors.forename: Fei
authors.initials: F
authors.lastname: Ru
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
authors.forename: Hao-Jui
authors.initials: HJ
authors.lastname: Weng
authors.forename: Yixun
authors.initials: Y
authors.lastname: Geng
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Undem
authors.forename: Marian
authors.initials: M
authors.lastname: Kollarik
authors.forename: Zhou-Feng
authors.initials: ZF
authors.lastname: Chen
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000009:adverse effects; D002738:Chloroquine / Q000009:adverse effects*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006632:Histamine / Q000009:adverse effects; D006801:Humans; D051379:Mice; D011537:Pruritus / Q000139:chemically induced*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects*
chemical_list: C546475:MrgprA3 protein, mouse; D043562:Receptors, G-Protein-Coupled; C510803:mas-related gene-X1 receptor, human; D006632:Histamine; D002738:Chloroquine; D002211:Capsaicin