Extracellular ATP and ADP mediate diverse physiological responses in mammalian cells, in part through the activation of G protein-coupled P2 purinoceptors. The cloning and expression of cDNAs encoding several P2 purinoceptor subtypes have enabled rapid advances in our understanding of the structural and functional properties of these receptors. The current report describes the isolation of a gene from a human genomic library that encodes a protein with the greatest similarity to the human P2U purinoceptor, a subtype that is distinguished by its ability to be activated by uridine nucleotides as well as adenine nucleotides. When expressed in a mammalian cell line, this novel receptor is activated specifically by UTP and UDP but not by ATP and ADP. Activation of this uridine nucleotide receptor resulted in increased inositol phosphate formation and calcium mobilization. Fluorescence in situ hybridization revealed that the gene encoding the uridine nucleotide receptor is located in region q13 of the X chromosome. Dendrogram analysis of the G protein-coupled P2 purinoceptors and the uridine nucleotide receptor indicates that these receptors belong to a family that may be more aptly named nucleotide receptors.