Disease relevance of P2RY4

• Therefore, we cloned and expressed the P2Y6 and P2Y4 receptors in 1321N1 human astrocytoma cells and compared their relative selectivities for UDP, UTP, and other uridine and adenine nucleotides with that of the P2Y2 receptor expressed in the same cells [1].
• P2Y4 receptors were found in basal cell carcinomas but not in squamous cell carcinomas [2].
• By contrast, the 6CFSMEo- submucosal cells expressed a UTP-specific response which displayed pharmacological characteristics compatible with the human P2Y4 receptor: in particular, there was no response to UDP or ATP and the UTP effect was totally inhibited by pertussis toxin [3].
• The metabotropic P2Y4 receptor participates in the commitment to differentiation and cell death of human neuroblastoma SH-SY5Y cells [4].
• In the meantime, one core test, the 3T3 neutral red uptake phototoxicity test (NRU PT) has been validated and has been accepted by ECVAM and the European Commission. The second core test, the red blood cell phototoxicity test (Photo-RBC test), has passed through a prevalidation process during this programme [5].

High impact information on P2RY4

• We report here the cloning and characterization of a 5173-bp P2P-related (P2P-R) cDNA that contains a 4214-bp open reading frame [6].
• The targeting signal of the P2Y2 receptor is located between the N terminus and 7TM, whereas that of the P2Y4 receptor is present in its C-terminal tail [7].
• Agonist-promoted regulation of the uridine nucleotide-activated human P2Y4 receptor (P2Y4-R) and P2Y6 receptor (P2Y6-R) was studied [8].
• Although addition of neither ATP nor UDP alone increased intracellular Ca2+ in 1321N1 human astrocytoma cells stably expressing the P2Y4 receptor, combined addition of these nucleotides resulted in a slowly occurring elevation of Ca2+ [9].
• Dendrogram analysis of the G protein-coupled P2 purinoceptors and the uridine nucleotide receptor indicates that these receptors belong to a family that may be more aptly named nucleotide receptors [10].

Biological context of P2RY4

• These data demonstrate that multiple P2Y receptors (P2Y1, P2Y2, and P2Y4 subtypes) are differentially involved in the regulation of proliferation in human keratinocytes and therefore may be important in wound healing [11].
• We have recently cloned from the human genome a new subtype of receptor (tentatively called P2Y4), which is structurally related to the P2U receptor [12].
• Fluorescence in situ hybridization revealed that the gene encoding the uridine nucleotide receptor is located in region q13 of the X chromosome [10].
• Differential regulation of the uridine nucleotide-activated P2Y4 and P2Y6 receptors. SER-333 and SER-334 in the carboxyl terminus are involved in agonist-dependent phosphorylation desensitization and internalization of the P2Y4 receptor [8].
• Nevertheless, a prolonged activation of the P2Y4 receptor by UTP also induced cell death, both in naive, differentiated, and P2Y4-transfected SH-SY5Y cells, as measured by direct count of intact nuclei and cytofluorimetric analysis of damaged DNA [4].

Anatomical context of P2RY4

• Human keratinocytes express multiple P2Y-receptors: evidence for functional P2Y1, P2Y2, and P2Y4 receptors [11].
• P2Y4 mRNA was detected in five cell lines: 1HAEo-, 16HBE14o-, 6CFSMEo-, HASMSC1 and CFPAC-1 [3].
• Our studies show that this new putative purinoceptor (designated P2P) is encoded by an intronless single copy gene that is exclusively expressed in pancreas, in contrast to the P2U and the P2Y purinoceptors which are widely distributed throughout the periphery [13].
• The results support the conclusion that regulation of K+ secretion across vestibular dark cell epithelium occurs by P2Y4 receptors without desensitization of the response [14].
• Tumor necrosis factor alpha-induced apoptosis in astrocytes is prevented by the activation of P2Y6, but not P2Y4 nucleotide receptors [15].

Associations of P2RY4 with chemical compounds

• Suramin acts as an antagonist at most P2Y-receptors with the exception of P2Y4- and tp2y-receptors [16].
• Activation of this uridine nucleotide receptor resulted in increased inositol phosphate formation and calcium mobilization [10].
• We then investigated which biological effects were mediated by the P2Y4 subtype and its physiological pyrimidine agonist UTP [4].
• Taken together these results describe the existence of a novel uridine nucleotide receptor that is not activated by adenine nucleotides [17].
• These data, in conjunction with results obtained by using the P2 receptor antagonists TNP-ATP, PPADS and MRS2179 indicate that the current response to alpha,beta-meATP is due to P2X3 receptor activation, while the ATP-induced rise in [Ca2+]i is evoked by P2Y1 and P2Y4 receptor activation [18].

Regulatory relationships of P2RY4

• Molecular cloning and characterization of a novel orphan receptor (P2P) expressed in human pancreas that shows high structural homology to the P2U purinoceptor [13].

Other interactions of P2RY4

• No signal was obtained for the P2Y1 and P2Y4 receptors [3].
• The data indicate that the P2Y2 receptor is activated with similar potencies by ATP and UTP but not by ADP or UDP; the P2Y6 receptor is activated most potently by UDP but weakly by UTP, ATP, and ADP; and the P2Y4 receptor is activated most potently by UTP, less potently by ATP, and not at all by nucleotide diphosphates [1].
• Selective antagonists for P2Y4 and P2Y14 receptors are still lacking [19].
• No mRNA transcripts for P2Y2 or P2Y4 were detectable in the P2Y11-expressing cells [20].
• Semi-quantitative real-time polymerase chain reaction revealed a developmental downregulation of mRNA levels for P2Y1 and P2Y4 receptors [21].

Analytical, diagnostic and therapeutic context of P2RY4

• RT-PCR and immunocytochemistry indicated the additional presence of endogenous P2Y1 and to some extent P2Y4 receptors [18].
• Single-cell reverse transcriptase-polymerase chain reaction revealed that P2Y1 and P2Y4 are prevailing receptors in TMN neurons [21].
• The NRU induced by jack bean urease was augmented by the addition of urea to cell culture medium; this suggests that urease-mediated NRU occurs via the generation of ammonia [22].
• There was a relatively good agreement between the NRU and in vivo patch test (r=0.648) [23].
• The features of the RT-CES assay, such as labeling free, automatic detection, and easy operation, give this assay potential to replace BALB/c 3T3 NRU assay and be used as routine setting for drug monitoring in the toxicological laboratory [24].

References