The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor.
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.
Ciana
Paolo
P
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Fumagalli
Marta
M
Trincavelli
Maria Letizia
ML
Verderio
Claudia
C
Rosa
Patrizia
P
Lecca
Davide
D
Ferrario
Silvia
S
Parravicini
Chiara
C
Capra
Valérie
V
Gelosa
Paolo
P
Guerrini
Uliano
U
Belcredito
Silvia
S
Cimino
Mauro
M
Sironi
Luigi
L
Tremoli
Elena
E
Rovati
G Enrico
GE
Martini
Claudia
C
Abbracchio
Maria P
MP
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*
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