Abstract
G protein-coupled receptors are the target of more than 30% of all FDA-approved drug therapies. Though the purinergic P2 receptors have been an attractive target for therapeutic intervention with successes such as the P2Y(12) receptor antagonist, clopidogrel, P2Y(2) receptor (P2Y(2)R) antagonism remains relatively unexplored as a therapeutic strategy. Due to a lack of selective antagonists to modify P2Y(2)R activity, studies using primarily genetic manipulation have revealed roles for P2Y(2)R in a multitude of diseases. These include inflammatory and autoimmune diseases, fibrotic diseases, renal diseases, cancer, and pathogenic infections. With the advent of AR-C118925, a selective and potent P2Y(2)R antagonist that became commercially available only a few years ago, new opportunities exist to gain a more robust understanding of P2Y(2)R function and assess therapeutic effects of P2Y(2)R antagonism. This review discusses the characteristics of P2Y(2)R that make it unique among P2 receptors, namely its involvement in five distinct signaling pathways including canonical Gα(q) protein signaling. We also discuss the effects of other P2Y(2)R antagonists and the pivotal development of AR-C118925. The remainder of this review concerns the mounting evidence implicating P2Y(2)Rs in disease pathogenesis, focusing on those studies that have evaluated AR-C118925 in pre-clinical disease models.