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The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl‐leukotrienes receptor
Author(s) -
Ciana Paolo,
Fumagalli Marta,
Trincavelli Maria Letizia,
Verderio Claudia,
Rosa Patrizia,
Lecca Davide,
Ferrario Silvia,
Parravicini Chiara,
Capra Valérie,
Gelosa Paolo,
Guerrini Uliano,
Belcredito Silvia,
Cimino Mauro,
Sironi Luigi,
Tremoli Elena,
Rovati G Enrico,
Martini Claudia,
Abbracchio Maria P
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601341
Subject(s) - receptor , biology , p2y receptor , g protein coupled receptor , adenylyl cyclase , orphan receptor , agonist , g protein , nucleotide , microbiology and biotechnology , biochemistry , pharmacology , transcription factor , gene
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 [ 35 S]GTPγS binding, was different from that of already known CysLT and P2Y receptors, with EC 50 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.