Identification of a uridine nucleotide-selective G-protein-linked receptor that activates phospholipase C.
Incubation of C6-2B rat glioma cells with UDP or UTP resulted in a time- and concentration-dependent increase in the accumulation of inositol phosphates. In contrast, ATP, ADP, and analogs of these nucleotides known to be effective agonists at P2U-, P2X-, P2Y-, P2T-, and P2Z-purinergic receptors all had no effect on inositol phosphate levels in C6-2B cells. Pyrimidine nucleotides stimulated inositol phosphate accumulation with an order of potency of UDP > 5-BrUTP > UTP > dTDP > UDP glucose. K0.5 values for UDP, 5-BrUTP, and UTP were 2.3 +/- 0.5, 9 +/- 3, and 57 +/- 10 microM, respectively. A similar uridine nucleotide selectivity was observed for arachidonic acid release presumably occurring as a consequence of activation of phospholipase A2. Cross-desensitization and additivity experiments indicated that UDP and UTP interact with the same population of receptors. The effect of uridine nucleotides on inositol phosphate accumulation was inhibited markedly by pretreatment of cells with pertussis toxin. UDP also caused a guanine nucleotide-dependent increase in inositol lipid hydrolysis in streptolysin-O-permeabilized cells. Taken together these results describe the existence of a novel uridine nucleotide receptor that is not activated by adenine nucleotides. This receptor is pharmacologically distinct from the previously described P2U- and other P2-purinergic receptors, and likely is a member of a new class of receptors for extracellular nucleotides.
Lazarowski
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Department of Pharmacology, University of North Carolina, School of Medicine, Chapel Hill 27599.
Harden
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D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D003110:Colonic Neoplasms; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005910:Glioma; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D007700:Kinetics; D037342:Pertussis Toxin; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D012265:Ribonucleotides / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism*; D014500:Uracil Nucleotides / Q000494:pharmacology*; D014530:Uridine Diphosphate / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007295:Inositol Phosphates; D011956:Receptors, Cell Surface; D012265:Ribonucleotides; D014500:Uracil Nucleotides; D010566:Virulence Factors, Bordetella; D016718:Arachidonic Acid; D014530:Uridine Diphosphate; D000255:Adenosine Triphosphate; D037342:Pertussis Toxin; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D014544:Uridine Triphosphate