title: UDP is a competitive antagonist at the human P2Y14 receptor.
abstract: G protein-coupled P2Y receptors (P2Y-R) are activated by adenine and uracil nucleotides. The P2Y(14) receptor (P2Y(14)-R) is activated by at least four naturally occurring UDP sugars, with UDP-glucose (UDP-Glc) being the most potent agonist. With the goal of identifying a competitive antagonist for the P2Y(14)-R, UDP was examined for antagonist activity in COS-7 cells transiently expressing the human P2Y(14)-R and a chimeric Galpha protein that couples Gi-coupled receptors to stimulation of phosphoinositide hydrolysis. UDP antagonized the agonist action of UDP-Glc, and Schild analysis confirmed that the antagonism was competitive (pK(B) = 7.28). Uridine 5'-O-thiodiphosphate also antagonized the human P2Y(14)-R (hP2Y(14)-R) with an apparent affinity similar to that of UDP. In contrast, no antagonist activity was observed with ADP, CDP, or GDP, and other uracil analogs also failed to exhibit antagonist activity. The antagonist activity of UDP was not observed at other hP2Y-R. In contrast to its antagonist action at the hP2Y(14)-R, UDP was a potent agonist (EC(50) = 0.35 muM) at the rat P2Y(14)-R. These results identify the first competitive antagonist of the P2Y(14)-R and demonstrate pharmacological differences between receptor orthologs.
authors.affiliation: Department of Pharmacology, University of North Carolina, CB#7365 Mary Ellen Jones Bldg., Chapel Hill, NC 27599-7365, USA.
authors.forename: Ingrid P
authors.initials: IP
authors.lastname: Fricks
authors.forename: Savitri
authors.initials: S
authors.lastname: Maddileti
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Carter
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Lazarowski
authors.forename: Robert A
authors.initials: RA
authors.lastname: Nicholas
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000235:genetics; D058470:Receptors, Purinergic P2Y; D014162:Transfection; D014530:Uridine Diphosphate / Q000378:metabolism*
chemical_list: C518528:P2Y14 receptor, human; C528912:P2Y14 receptor, rat; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y; D014530:Uridine Diphosphate