journal club 2015.12.31

Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus

Qin Liu,1 Zongxiang Tang,1 Lenka Surdenikova,2,4 Seungil Kim,5 Kush N. Patel,1 Andrew Kim,1 Fei Ru,2 Yun Guan,3
Hao-Jui Weng,1 Yixun Geng,1 Bradley J. Undem,2 Marian Kollarik,2 Zhou-Feng Chen,5 David J. Anderson,6,7
and Xinzhong Dong1,7,*

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.

2.Sensory Neuron-Specific GPCR Mrgprs