Based on sequence similarity, the superfamily of G protein-coupled receptors (GPRs) can be subdivided into several subfamilies, the members of which often share similar ligands. The sequence data provided by the human genome project allows us to identify new GPRs by in silico homology screening, and to predict their ligands.

By searching the human genomic database with known nucleotide receptors we discovered the gene for GPR99, a new orphan GPR. The mRNA of GPR99 was found in kidney and placenta. Phylogenetic analysis groups GPR99 into the P2Y subfamily of GPRs. Based on the phylogenetic tree we propose a new classification of P2Y nucleotide receptors into two subgroups predicting a nucleotide ligand for GPR99. By assaying known nucleotide ligands on heterologously expressed GPR99, we could not identify specifically activating substances, indicating that either they are not agonists of GPR99 or that GPR99 was not expressed at the cell surface. Analysis of the chromosomal localization of all genes of the P2Y subfamily revealed that all members of subgroup "a" are encoded by less than 370 kb on chromosome 3q24, and that the genes of subgroup "b" are clustered on one hand to chromosome 11q13.5 and on the other on chromosome 3q24-25.1 close to the subgroup "a" position. Therefore, the P2Y subfamily is a striking example for local gene amplification.

We identified a new orphan receptor, GPR99, with homology to the family of G protein-coupled nucleotide receptors. Phylogenetic analysis separates this family into different subgroups predicting a nucleotide ligand for GPR99.