The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor

Paolo Ciana, Marta Fumagalli, Maria Letizia Trincavelli, Claudia Verderio, Patrizia Rosa, Davide Lecca, Silvia Ferrario, Chiara Parravicini, Valérie Capra, Paolo Gelosa, Uliano Guerrini, Silvia Belcredito, Mauro Cimino, Luigi Sironi, Elena Tremoli, G. Enrico Rovati, Claudia Martini, Maria P. Abbracchio

Research output: Contribution to journalArticle

Abstract

Nucleotides and cysteinyl-leukotrienes (CysLTs) are unrelated signaling molecules inducing multiple effects through separate G-protein-coupled receptors: the P2Y and the CysLT receptors. Here we show that GPR17, a Gi-coupled orphan receptor at intermediate phylogenetic position between P2Y and CysLT receptors, is specifically activated by both families of endogenous ligands, leading to both adenylyl cyclase inhibition and intracellular calcium increases. Agonist-response profile, as determined by [35S] GTPγS binding, was different from that of already known CysLT and P2Y receptors, with EC50 values in the nanomolar and micromolar range, for CysLTs and uracil nucleotides, respectively. Both rat and human receptors are highly expressed in the organs typically undergoing ischemic damage, that is, brain, heart and kidney. In vivo inhibition of GPR17 by either CysLT/P2Y receptor antagonists or antisense technology dramatically reduced ischemic damage in a rat focal ischemia model, suggesting GPR17 as the common molecular target mediating brain damage by nucleotides and CysLTs. In conclusion, the deorphanization of GPR17 revealed a dualistic receptor for two endogenous unrelated ligand families. These findings may lead to dualistic drugs of previously unexplored therapeutic potential.

Original languageEnglish
Pages (from-to)4615-4627
Number of pages13
JournalEMBO Journal
Volume25
Issue number19
DOIs
Publication statusPublished - Oct 4 2006

Keywords

  • Cysteinyl-leukotrienes
  • Extracellular nucleotides
  • G-protein-coupled receptors
  • GPR17
  • Neuroinflammation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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  • Cite this

    Ciana, P., Fumagalli, M., Trincavelli, M. L., Verderio, C., Rosa, P., Lecca, D., Ferrario, S., Parravicini, C., Capra, V., Gelosa, P., Guerrini, U., Belcredito, S., Cimino, M., Sironi, L., Tremoli, E., Rovati, G. E., Martini, C., & Abbracchio, M. P. (2006). The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO Journal, 25(19), 4615-4627. https://doi.org/10.1038/sj.emboj.7601341