P2 Receptors Activated by Uracil Nucleotides - An Update

Abstract

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, P2Y2, P2Y4, P2Y6 and P2Y14. P2Y2 and P2Y4 receptors are activated by UTP (the P2Y2, and the rat but not the human P2Y4 receptor are also activated by ATP), the P2Y6 receptor is activated by UDP, and the P2Y14 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 P2Y2, P2Y4, and P2Y6 receptor activation results in stimulation of phospholipase C, the P2Y14 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 P2Y2 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 P2Y2 and P2Y6 receptors that appear to be selective versus other P2Y receptor subtypes have recently been described. Selective antagonists for P2Y4 and P2Y14 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. Müller published in Curr. Pharm. Des. 2002, 8, 2353-2369.

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

“…Suramin and RB-2 are potent inhibitors of all P2Y subtypes expressed in HUVECs (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 and P2Y 11 ) with the exception of P2Y 4 that is insensitive to suramin (Brunschweiger and Muller, 2006). To further define the P2Y receptor involved, the selective antagonists of P2Y 1 , P2Y 6 and P2Y 11 (MRS2500, MRS2578 and NF157, respectively) were tested on LPS-induced neutrophil TEM.…”

Synthesis, characterization, and in vitro evaluation of the selective P2Y2 receptor antagonist AR-C118925

“…One of the most selective antagonists described to date is the thiouracil derivative 5- Fig. 1) [26,27], which has been developed by structural modifications of the physiological agonist UTP [28]. Replacement of the ribose triphosphate moiety and derivatization of the uracil ring in UTP (1b) eliminated agonist properties and improved potency and pharmacokinetic properties, respectively [28].…”

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…Purinoceptors Two families of purinergic receptors known as P1 and P2 (for ADO and ATP/ADP, respectively) were postulated almost 40 years ago (in 1978); however, it has been proposed the existence of another subfamily of receptors activated by the nucleobase adenine named P0 receptors [18].…”

“…In addition, ADORA1 activation can directly activate K + channels and inhibit Q-, P-and N-type Ca 2+ channels [24]. The proposed P0 receptors are also GPCR, the first one was cloned in 2002 from rat tissue [25], recently has been cloned from, mouse and guinea pig [26,27], P0 receptor are mainly coupled to Gi protein and in consequence to the inhibition of adenylate cyclase [18,25,26], and are expressed in lung, ovaries, kidneys, and nervous system [25].…”