Rehabilitation of the P2X5 receptor: a re-evaluation of structure and function

Abstract

Of the extended family of ATP-gated P2X ion-channels, the P2X5 receptor has received comparatively little attention since first cloned over 25 years ago. Disinterest in studying this P2X subtype stems from two commonly held beliefs: (i) canonical human P2X5 is non-functional because the P2X5 subunit is truncated (hP2X5A, 422 aa) and missing the critical peptide sequence (22 aa) encoded by exon 10; (ii) rat and mouse P2X5 subunits are fully formed (455 aa) but the receptor is only weakly functional, and successive ATP responses rapidly run down in amplitude. However, newer studies have re-evaluated these notions. First, a low proportion (around 10%) of humans possess full-length P2X5 subunits (444 aa) and can form competent P2X5 receptors. Full-length P2X5 has been identified only in black Americans, but may occur in a wider population as more ethnicities are screened. Second, replacement of one of three amino acids in rat P2X5 subunits with corresponding residues in human P2X5 subunits (V67I, S191F, or F195H) significantly improves the responsiveness of rat P2X5 to ATP. Replaced residues exert an allosteric action on the left flipper, allowing the docking jaw for ATP to flex the lower body of the subunit and fully open the ion pore. This proposed action may drive the search for naturally occurring modulators which act allosterically on wildtype rat P2X5. This review collates the available information on the structure and function of human and rat P2X5 receptors, with the view to rehabilitating the reputation of these ATP-gated ion channels and stimulating future lines of research.

Brain cell-type shifts in Alzheimer’s disease, autism, and schizophrenia interrogated using methylomics and genetics

“…P2RX5 encodes the P2X5 purinergic receptor, a ligand-gated ion channel activated by ATP, which contributes to endothelial cell differentiation and autocrine regulation ( 49 , 50 ), and has functional roles in adult mouse astrocytes ( 51 ). Common genetic variation plausibly contributes to P2X5 receptor function: Due to a SNV that promotes exon skipping, only a proportion of the human population express fully functional P2X5 receptors, and amino acid substitutions within this gene can markedly affect the receptor’s responsiveness to its ATP ligand ( 52 ). TRPV3 is a nonselective cation channel, whose activation induces endothelium-mediated vasodilation of cerebral arteries ( 53 ) and cerebral parenchymal arterioles, which regulate blood flow from larger pial arteries on the brain surface to capillary beds ( 54 ).…”