CaltechAUTHORS
Published December 24, 2009 | Version Supplemental Material + Accepted Version
Journal Article Open

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

Creators

  • 1. ROR icon Johns Hopkins University
  • 2. ROR icon Washington University in St. Louis
  • 3. ROR icon California Institute of Technology
  • 4. ROR icon Howard Hughes Medical Institute

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.

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.

Attached Files

Accepted Version - nihms168104.pdf

Supplemental Material - mmc1.pdf

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Additional details

Identifiers

PMCID
PMC2989405
Eprint ID
17207
DOI
10.1016/j.cell.2009.11.034
Resolver ID
CaltechAUTHORS:20100119-100309565

Related works

Describes
10.1016/j.cell.2009.11.034 (DOI)

Funding

Alfred P. Sloan Foundation
Whitehall Foundation
Johns Hopkins Blaustein Pain Research Fund
NIH
NS054791
NIH
HL038095
NIH
DK074480
NIH
AR056318
NIH
NS048499
VEGA
1/0018/08
Howard Hughes Medical Institute (HHMI)

Dates

Created
2010-01-26
Created from EPrint's datestamp field
Updated
2021-11-08
Created from EPrint's last_modified field