A critical look at the function of the P2Y11 receptor

Abstract

The P2Y 11 receptor is a member of the purinergic receptor family. It has been overlooked, somewhat due to the lack of a P2ry11 gene orthologue in the murine genome, which prevents the generation of knockout mice, which have been so helpful for defining the roles of other P2Y receptors. Furthermore, some of the studies reported to date have methodological shortcomings, making it difficult to determine the function of P2Y 11 with certainty. In this review, we discuss the lack of a murine BP2Y 11 -like receptor^and highlight the limitations of the currently available methods used to investigate the P2Y 11 receptor. These methods include protein recognition with antibodies that show very little specificity, gene expression studies that completely overlook the existence of a fusion transcript between the adjacent PPAN gene and P2RY11, and agonists/antagonists reported to be specific for the P2Y 11 receptor but which have not been tested for activity on numerous other adenosine 5′-triphosphate (ATP)-binding receptors. We suggest a set of criteria for evaluating whether a dataset describes effects mediated by the P2Y 11 receptor. Following these criteria, we conclude that the current evidence suggests a role for P2Y 11 in immune activation with cell typespecific effects.

P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

“…One of the major problems we face is that the murine genome does not have a human P2Y11R orthologue, and there is no available P2Y11R specific knockout mouse model. Some other preclinical studies were based on rats, but still provided only a limited understanding of this receptor . In rats, NF340 has been shown to act on glial cells and participate in the maintenance of neuropathic pain .…”

“…P2Y11R is present on several immune cells such as lymphocytes, mast cells, granulocytes, and dendritic cells. P2Y11R has been reported to be involved in the migration, differentiation, and other functions of immune cells . Currently, there are several available P2Y11R ligands and antagonists.…”

“…NF340 is known to display 520‐fold higher selectivity for P2Y11 than other P2Y family receptors . Therefore, NF340 has been used in recent studies to investigate the physiological role of P2Y11R . Treatment with NF340 has been reported to prevent ATP‐induced stimulation of cell migration and Ca 2+ signaling in human hepatocellular carcinoma cells .…”

“…P2Y11R has been reported to be involved in the migration, differentiation, and other functions of immune cells. 13 Currently, there are several available P2Y11R ligands and antagonists. Among them, NF340 is a newly developed, highly potent, and selective P2Y11R antagonist.…”

Adenosine diphosphate–sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators

“…Interestingly, P2Y11 was the most abundant form of P2Y receptor expressed in HUVECs and ADP significantly upregulated the gene and protein expression of P2Y11. Besides, ADP is a partial agonist for P2Y11 receptor, even in the canine P2Y11 receptor, which is 70% homologous to the human receptor, is more potently activated by ADP than ATP . Therefore, it is tempting to speculate that P2Y11 receptor plays a key role in the inhibition of endothelial proliferation induced by ADP.…”