Insights into the Molecular Mechanisms Underlying Mammalian P2X7 Receptor Functions and Contributions in Diseases, Revealed by Structural Modeling and Single Nucleotide Polymorphisms

Abstract

The mammalian P2X7 receptors (P2X7Rs), a member of the ionotropic P2X receptor family with distinctive functional properties, play an important part in mediating extracellular ATP signaling in health and disease. A clear delineation of the molecular mechanisms underlying the key receptor properties, such as ATP-binding, ion permeation, and large pore formation of the mammalian P2X7Rs, is still lacking, but such knowledge is crucial for a better understanding of their physiological functions and contributions in diseases and for development of therapeutics. The recent breakthroughs in determining the atomic structures of the zebrafish P2X4.1R in the closed and ATP-bound open states have provided the long-awaited structural information. The human P2RX7 gene is abundant with non-synonymous single nucleotide polymorphisms (NS-SNPs), which generate a repertoire of human P2X7Rs with point mutations. Characterizations of the NS-SNPs identified in patients of various disease conditions and the resulting mutations have informed previously unknown molecular mechanisms determining the mammalian P2X7R functions and diseases. In this review, we will discuss the new insights into such mechanisms provided by structural modeling and recent functional and genetic linkage studies of NS-SNPs.

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

“…S6B). Several polymorphisms have been described for the P2RX7 gene and their impact on the P2RX7 function, the mechanisms and relationship with diseases were characterized for a number of mutants (45)(46)(47). Surprisingly, none of these variants were found in a metaanalysis of IBD (CD and UC) that included a Genome-Wide Association study (48).…”

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

“…They assemble into trimeric ligandgated cation-permeable ion channel complexes that can be activated by extracellular adenosine 5′-triphosphate (ATP) (for review, see [1,2]). The P2X7 receptor, predominantly expressed in cells of hematopoietic lineages, including macrophages, lymphocytes and microglia, seems to be the most divergent member of the P2X receptor family in terms of its individual structure, pharmacology and function [3,4]. Besides its large size (595 amino acids) and long cytoplasmic C terminus that may interact with other signalling proteins, activation of this subtype requires rather high concentrations of extracellular ATP.…”