Update of P2X receptor properties and their pharmacology: IUPHAR Review 30.

Peter Illes,Annette Nicke,Stanko S Stojilkovic,Francesco Di Virgilio,Christa E Müller,Kenneth A Jacobson,Brian F King,Samuel J Fountain,Thomas Grutter,Charles Kennedy,Günther Schmalzing,Michael F Jarvis

doi:10.1111/bph.15299

Abstract

The known seven mammalian receptor subunits (P2X1–7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighbouring subunits. In addition to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).

Highlights

The known seven mammalian receptor subunits (P2X1–7) form cationic channels gated by ATP
P2X receptors appear very early in phylogeny, and it is a fascinating property of these primitive receptors that, in contrast to their mammalian counterparts, they are expressed predominantly or even exclusively intracellularly
Our knowledge of P2X receptor structure/function has greatly increased in the four decades elapsing since their discovery

Summary

IUPHAR REVIEW

Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as Abbreviations: AD, Alzheimer's disease; BBB, blood–brain barrier; BzATP, dibenzoyl-ATP; DRG, dorsal root ganglion; h, human; KO, knockout; m, mouse; NANC, non-adrenergic, non-cholinergic; PAM, positive allosteric modulator; r, rat; SE, status epilepticus; SNP, single nucleotide polymorphism; TM, transmembrane; TNP-ATP, trinitrophenyl-ATP; α,β-meATP, α,β-methylene ATP. KEYWORDS (patho)physiological functions, agonists, antagonists, extracellular ATP, knockout mice, ligandgated cationic channels, P2X receptors

| INTRODUCTION

Aurintricarboxylic acid

Immune cells

Findings

13 | CONCLUSIONS