View the Current Issue

Article

  • The EMBO Journal (2006) 25, 4615 - 4627
  • doi:10.1038/sj.emboj.7601341

Published online: 21 September 2006

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

Paolo Ciana1,a, Marta Fumagalli1,a, Maria Letizia Trincavelli2,a, Claudia Verderio3, Patrizia Rosa3, Davide Lecca1, Silvia Ferrario1, Chiara Parravicini1, Valérie Capra1, Paolo Gelosa1, Uliano Guerrini1, Silvia Belcredito1, Mauro Cimino4, Luigi Sironi1, Elena Tremoli1,5, G Enrico Rovati1, Claudia Martini2 and Maria P Abbracchio1

  1. Department of Pharmacological Sciences, University of Milan, Milan, Italy
  2. Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy
  3. Department of Medical Pharmacology, CNR Institute of Neuroscience, Cellular and Molecular Pharmacology, University of Milan, Milan, Italy
  4. Institute of Pharmacology and Pharmacognosy, University of Urbino, Urbino, Italy
  5. Monzino Cardiologic Center IRCCS, Milan, Italy

Correspondence to:

Maria P Abbracchio, Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, Milan 20133, Italy. Tel.: +390 250 318 310; Fax: +390 250 318 284; E-mail: mariapia.abbracchio@unimi.it

aThese authors contributed equally to this work

Received 3 April 2006; Accepted 22 August 2006

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]GTPgammaS 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.

  • Keywords:

    • cysteinyl-leukotrienes,
    • extracellular nucleotides,
    • G-protein-coupled receptors,
    • GPR17,
    • neuroinflammation