Significance of P2X7 Receptor Variants to Human Health and Disease

Abstract

The human P2X7 receptor is a trimeric ligand-gated cation channel coded by the P2XR7 gene located at chromosome position 12q24. P2X7 is expressed in a wide variety of normal and disease-associated cell types. Activation of this receptor by extracellular adenosine 5'-triphosphate results in numerous downstream events including the release of pro-inflammatory mediators, cell proliferation or death, and killing of intracellular pathogens. As a result, P2X7 plays important roles in inflammation, immunity, bone homeostasis, neurological function and neoplasia. The P2XR7 gene encodes a P2X7 subunit 595 amino acids in length, however splice isoforms that can alter receptor expression and function, and modify the signaling properties downstream of receptor activation also exist. Moreover, the relative amount of P2X7 function varies between human individuals due to numerous single nucleotide polymorphisms resulting in either loss- or gain-of-function. Combinations of these polymorphisms give rise to various haplotypes that can also modify P2X7 function. Collectively, P2X7, and its splice and polymorphic variants are attracting considerable interest in relation to human health and disease, including the development and publication of a number of patents.

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

“…The receptor exists in several splice isoforms (A–J) and single nucleotide polymorphisms (SNPs) correlate with several diseases 11, 12. The P2X7R is a ligand‐gated ion channel permeable to Ca 2+ , K + and Na + 13.…”

Natural compounds with P2X7 receptor-modulating properties

“…Therefore, this receptor may play an important role in the development of various diseased states, including inflammation, neuropathic pain and a number of neurological disorders [7][8][9]. In addition, P2X7 splice variants may alter receptor expression and function [10]. Furthermore, both loss-of-function and gain-of-function P2X7 polymorphisms have been described.…”

“…Furthermore, both loss-of-function and gain-of-function P2X7 polymorphisms have been described. Some of them are associated with different pathologies, including tuberculosis, Crohn's disease or bipolar affective disorders (reviewed by [10]). Genetically engineered mouse models lacking P2X7 expression in distinct tissues showed an attenuation of the release of pro-inflammatory cytokines [11], thereby decreasing the incidence and severity of arthritis [12] and reducing inflammatory and neuropathic pain sensitivity [13].…”

Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

“…P2X7 can be inhibited by broad-spectrum antagonists, including pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), Reactive Blue 2 and suramin, and by more specific antagonists, including Brilliant Blue G (BBG), KN-62, oxidised ATP and A 438079 [9]. P2X7 activity varies between human individuals and mouse strains due to single nucleotide polymorphisms, resulting in loss or gain of function variants, which can be used to establish the role of this receptor in nucleotide-induced responses [11]. P2Y2 is present on neural, bone, epithelial, endothelial, immune and renal cell types [12].…”