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

Qin Liu, Zongxiang Tang, Lenka Surdenikova, Seungil Kim, Kush N. Patel, Andrew Kim, Fei Ru, Yun Guan, Hao Jui Weng, Yixun Geng, Bradley J. Undem, Marian Kollarik, Zhou Feng Chen, David J. Anderson, Xinzhong Dong

Research output: Contribution to journalArticle

432 Scopus citations

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.

Original languageEnglish
Pages (from-to)1353-1365
Number of pages13
JournalCell
Volume139
Issue number7
DOIs
StatePublished - Dec 24 2009

Keywords

  • HUMDISEASE
  • MOLNEURO

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    Liu, Q., Tang, Z., Surdenikova, L., Kim, S., Patel, K. N., Kim, A., Ru, F., Guan, Y., Weng, H. J., Geng, Y., Undem, B. J., Kollarik, M., Chen, Z. F., Anderson, D. J., & Dong, X. (2009). Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus. Cell, 139(7), 1353-1365. https://doi.org/10.1016/j.cell.2009.11.034