PT  - JOURNAL ARTICLE
AU  - Ai-Dong Qi
AU  - T. Kendall Harden
AU  - Robert A. Nicholas
TI  - Is GPR17 a P2Y/Leukotriene Receptor? Examination of Uracil Nucleotides, Nucleotide Sugars, and Cysteinyl Leukotrienes as Agonists of GPR17
AID  - 10.1124/jpet.113.207647
DP  - 2013 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 38--46
VI  - 347
IP  - 1
4099  - http://jpet.aspetjournals.org/content/347/1/38.short
4100  - http://jpet.aspetjournals.org/content/347/1/38.full
SO  - J Pharmacol Exp Ther2013 Oct 01; 347
AB  - The orphan receptor GPR17 has been reported to be activated by UDP, UDP-sugars, and cysteinyl leukotrienes, and coupled to intracellular Ca2+ mobilization and inhibition of cAMP accumulation, but other studies have reported either a different agonist profile or lack of agonist activity altogether. To determine if GPR17 is activated by uracil nucleotides and leukotrienes, the hemagglutinin-tagged receptor was expressed in five different cell lines and the signaling properties of the receptor were investigated. In C6, 1321N1, or Chinese hamster ovary (CHO) cells stably expressing GPR17, UDP, UDP-glucose, UDP-galactose, and cysteinyl leukotriene C4 (LTC4) all failed to promote inhibition of forskolin-stimulated cAMP accumulation, whereas both UDP and UDP-glucose promoted marked inhibition (>80%) of forskolin-stimulated cAMP accumulation in C6 and CHO cells expressing the P2Y14 receptor. Likewise, none of these compounds promoted accumulation of inositol phosphates in COS-7 or human embryonic kidney 293 cells transiently transfected with GPR17 alone or cotransfected with Gαq/i5, which links Gi-coupled receptors to the Gq-regulated phospholipase C (PLC) signaling pathway, or PLCε, which is activated by the Gα12/13 signaling pathway. Moreover, none of these compounds promoted internalization of GPR17 in 1321N1-GPR17 cells. Consistent with previous reports, coexpression experiments of GPR17 with cysteinyl leukotriene receptor 1 (CysLTR1) suggested that GPR17 acts as a negative regulator of CysLTR1. Taken together, these data suggest that UDP, UDP-glucose, UDP-galactose, and LTC4 are not the cognate ligands of GPR17.