P2 receptors activated by uracil nucleotides - An update

Pyrimidine nucleotides, including UTP, UDP and UDP-glucose, are important signaling molecules which activate G protein-coupled membrane receptors (GPCRs) of the P2Y family. Four distinct pyrimidine nucleotide-sensitive P2Y receptor subtypes have been cloned, P2Y(2), P2Y(4), P2Y(6) and P2Y(14). P2Y(2) and P2Y(4) receptors are activated by UTP (the P2Y(2), and the rat but not the human P2Y(4) receptor are also activated by ATP), the P2Y(6) receptor is activated by UDP, and the P2Y(14) receptor by UDP-glucose. Furthermore. non-P2Y GPCRs, the cysteinylleukotriene receptors (CysLT1R and CysLT2R) have been described to be activated by UDP in addition to activation by cysteinylleukotrienes. While P2Y(2), P2Y(4), and P2Y(6) receptor activation results in stimulation of phospholipase C, the P2Y(14) receptor is coupled to inhibition of adenylate cyclase. Derivatives and analogs of the physiological nucleotides UTP, UDP and ATP have been synthesized and evaluated in order to obtain enzymatically stable, subtype-selective agonists. The P2Y(2) receptor agonists diuridine tetraphosphate (diquafosol) and the uracil-cytosine dinucleotide denufosol are currently undergoing clinical trials for dry eye disease, retinal detachment disease, upper respiratory tract symptoms, and cystic fibrosis. respectively. The first antagonists for P2Y(2) and P2Y(6) receptors that appear to be selective versus other P2Y receptor subtypes have recently been described. Selective antagonists for P2Y(4) and P2Y(14) receptors are still lacking. Uracil nucleotide-sensitive P2Y receptor subtypes may constitute future targets for the treatment of certain cancer types, vascular diseases, inflammatory diseases, and immunomodulatory intervention. They have also been proposed to play a role in neurodegenerative diseases. This article is an updated version of P2-Pyrimidinergic Receptors and Their Ligands by C. E. Muller published in Curr. Pharm. Des. 2002, 8, 2353-2369.