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 tim e- and concentration-dependent increase in the accumulation of inosito l phosphates. In contrast, ATP, ADP, and analogs of these nucleotides known to be effective agonists at P-2U-, P-2X-, P-2Y-, P,(2T)-, and P- 2Z-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. K-0.5 values for UDP, 5-BrUTP, and UTP were 2.3 +/- 0.5, 9 +/- 3, and 57 +/- 10 mu M, respectively. A similar uridine nucleotid e selectivity was observed for arachidonic acid release presumably occ urring as a consequence of activation of phospholipase A(2). Cross-des ensitization and additivity experiments indicated that UDP and UTP int eract with the same population of receptors. The effect of uridine nuc leotides on inositol phosphate accumulation was inhibited markedly by pretreatment of cells with pertussis toxin. UDP also caused a guanine nudeotide-dependent increase in inositol lipid hydrolysis in streptoly sin-O-permeabilized cells. Taken together these results describe the e xistence of a novel uridine nucleotide receptor that is not activated by adenine nucleotides. This receptor is pharmacologically distinct fr om the previously described P-2U- and other P-2-purinergic receptors, and likely is a member of a new class of receptors for extracellular n ucleotides.