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

Liu, Qin and Tan, Zongxiang and Surdenikova, Lenka and Kim, Seungil and Patel, Kush N. and Kim, Andrew and Ru, Fei and Guan, Yun and Weng, Hao-Jui and Geng, Yixun and Undem, Bradley J. and Kollarik, Mariam and Chen, Zhou-Feng and Anderson, David J. and Dong, Xinzhong (2009) Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus. Cell, 139 (7). pp. 1353-1365. ISSN 0092-8674. http://resolver.caltech.edu/CaltechAUTHORS:20100119-100309565

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.cell.2009.11.034 DOIUNSPECIFIED
Additional Information:© 2009 Elsevier Inc. Received 17 December 2008; revised 14 September 2009; accepted 4 November 2009. Published online: December 10, 2009. Available online 10 December 2009. We thank Shirley Pease and the staff of the Caltech transgenic mouse facility for assistance with embryonic stem cell manipulation. We also thank M. Ringkamp and R. Meyer for helpful comments on the manuscript. The work was supported by an Alfred P. Sloan Neuroscience grant, a Whitehall Foundation grant, a Blaustein Pain Research Fund award, and grants from the National Institutes of Health to X.D. (NS054791), B.J.U. (HL038095), M.K. (DK074480), Z.F.C. (AR056318), and D.J.A. (NS048499). L.S. is supported by VEGA 1/ 0018/08. D.J.A and X.D. are an Investigator and an Early Career Scientist of the Howard Hughes Medical Institute, respectively.
Funders:
Funding AgencyGrant Number
Alfred P. Sloan Neuroscience UNSPECIFIED
Whitehall Foundation UNSPECIFIED
Blaustein Pain Research FundUNSPECIFIED
NIHNS054791
NIHHL038095
NIHDK074480
NIHAR056318
NIHNS048499
VEGA 1/0018/08
Subject Keywords:molneuro; humdisease
Record Number:CaltechAUTHORS:20100119-100309565
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20100119-100309565
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17207
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:26 Jan 2010 17:01
Last Modified:26 Dec 2012 11:42

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