title: The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor.
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 [(35)S]GTPgammaS 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.
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciana
authors.forename: Marta
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rosa
authors.forename: Davide
authors.initials: D
authors.lastname: Lecca
authors.forename: Silvia
authors.initials: S
authors.lastname: Ferrario
authors.forename: Chiara
authors.initials: C
authors.lastname: Parravicini
authors.forename: Valérie
authors.initials: V
authors.lastname: Capra
authors.forename: Paolo
authors.initials: P
authors.lastname: Gelosa
authors.forename: Uliano
authors.initials: U
authors.lastname: Guerrini
authors.forename: Silvia
authors.initials: S
authors.lastname: Belcredito
authors.forename: Mauro
authors.initials: M
authors.lastname: Cimino
authors.forename: Luigi
authors.initials: L
authors.lastname: Sironi
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.forename: G Enrico
authors.initials: GE
authors.lastname: Rovati
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000139:chemically induced; D019556:COS Cells; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D020539:Sequence Analysis, Protein; D014500:Uracil Nucleotides / Q000378:metabolism*
chemical_list: C121670:GPR17 protein, human; C514731:GPR17 protein, rat; D015289:Leukotrienes; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; D018077:Receptors, Leukotriene; D018048:Receptors, Purinergic P2; D014500:Uracil Nucleotides; C112381:cysteinyl-leukotriene; D003545:Cysteine; C083169:leukotriene D4 receptor