That was then, this is now: the development of our knowledge and understanding of P2 receptor subtypes

Charles Kennedy

doi:10.1007/s11302-021-09763-0

Abstract

P2 receptors are present in virtually all tissues and cell types in the human body, and they mediate the physiological and pharmacological actions of extracellular purine and pyrimidine nucleotides. They were first characterised and named by Geoff Burnstock in 1978, then subdivided into P2X and P2Y purinoceptors in 1985 on the basis of pharmacological criteria in functional studies on native receptors. Molecular cloning of receptors in the 1990s revealed P2X receptors to comprise seven different subunits that interact to produce functional homo- and heterotrimeric ligand-gated cation channels. A family of eight P2Y G protein–coupled receptors were also cloned, which can form homo- and heterodimers. Deep insight into the molecular mechanisms of agonist and antagonist action has been provided by more recent determination of the tertiary and quaternary structures of several P2X and P2Y receptor subtypes. Agonists and antagonists that are highly selective for individual subtypes are now available and some are in clinical use. This has all come about because of the intelligence, insight and drive of the force of nature that was Geoff Burnstock.

Highlights

I first met Geoff Burnstock on 5 May 1981, when he interviewed me for a PhD position
I performed some experiments using the guinea pig taenia coli, the tissue that had contributed so much to me being at UCL, but they came to nothing and I moved on to portal vein, which, at that time, in the rabbit was the best example of purinergic inhibitory neurotransmission outside of the gastrointestinal tract [19, 20]
Tertiary structures Determination of the crystal structures of the human P2Y1R [73] and P2Y12R [74, 75] in ligand-bound states at resolutions of 2.2–3.1 Å provided detailed insight into their tertiary structures and how agonists and antagonists interact with them to produce their effects. They confirm that both subtypes have the canonical seven transmembrane spanning regions (TMR) of G protein–coupled receptors (GPCR), linked by three extracellular loops (ECL) and three intracellular loops, but they are, structurally distinct

Summary

Introduction

I first met Geoff Burnstock on 5 May 1981, when he interviewed me for a PhD position. Evidence was published that the agonists, β,γ-methylene-L-ATP and ADP-β-F, displayed selectivity for P2X and P2Y purinoceptors respectively It would be some time before subtype-selective antagonists became available, but the introduction of suramin as the first, easy to use, non-selective P2 purinoceptor antagonist was a major development for purinergic research in general. Tertiary structures Determination of the crystal structures of the human P2Y1R [73] and P2Y12R [74, 75] in ligand-bound states at resolutions of 2.2–3.1 Å provided detailed insight into their tertiary structures and how agonists and antagonists interact with them to produce their effects They confirm that both subtypes have the canonical seven TMR of GPCR, linked by three extracellular loops (ECL) and three intracellular loops, but they are, structurally distinct.

Antagonist binding sites

Findings

Conclusion