Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
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.
Liu
Qin
Q
The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Tang
Zongxiang
Z
Surdenikova
Lenka
L
Kim
Seungil
S
Patel
Kush N
KN
Kim
Andrew
A
Ru
Fei
F
Guan
Yun
Y
Weng
Hao-Jui
HJ
Geng
Yixun
Y
Undem
Bradley J
BJ
Kollarik
Marian
M
Chen
Zhou-Feng
ZF
Anderson
David J
DJ
Dong
Xinzhong
X
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*
C546475:MrgprA3 protein, mouse; D043562:Receptors, G-Protein-Coupled; C510803:mas-related gene-X1 receptor, human; D006632:Histamine; D002738:Chloroquine; D002211:Capsaicin