Identification of a Novel Human ADP Receptor Coupled to G_i*

Abstract

We have cloned and expressed a novel human G-protein-coupled receptor closely related to the human P2Y₁₂ receptor. It corresponds to the orphan receptor called GPR86. GPR86 proved to be a G_i-coupled receptor displaying a high affinity for ADP, similar to the P2Y₁₂receptor and can therefore be tentatively called P2Y₁₃. In 1321N1 cells, the P2Y₁₃ receptor coupled to the phosphoinositide pathway only when coexpressed with Gα₁₆. Inositol trisphosphate formation was stimulated equipotently by nanomolar concentrations of ADP and 2MeSADP, whereas 2MeSATP and ATP were inactive. In CHO-K1 cells expressing the P2Y₁₃ receptor, ADP and 2MeSADP had a biphasic effect on the forskolin-stimulated accumulation of cAMP: inhibition at nanomolar concentrations and potentiation at micromolar levels. In the same cells, ADP and 2MeSADP also stimulated the phosphorylation of Erk1 and Erk2, in a pertussis toxin-sensitive way. The tissue distribution of P2Y₁₃ was investigated by reverse transcriptase-polymerase chain reaction, and the predominant signals were obtained in spleen and brain. Although these can be discriminated by tissue distribution and some pharmacological features, the P2Y₁₂and P2Y₁₃ receptors form a subgroup of related P2Y subtypes that is structurally different from the other P2Y subtypes but share coupling to G_i and a high affinity for ADP.