The P2X1 receptor as a therapeutic target

Abstract

Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function. Specifically, the P2X1 receptor has been implicated in controlling smooth muscle contractions of the vas deferens and therefore has emerged as an exciting drug target for male contraception. In addition, the P2X1 receptor contributes to smooth muscle contractions of the bladder and is a target to treat bladder dysfunction. Finally, platelets and neutrophils have populations of P2X1 receptors that could be targeted for thrombosis and inflammatory conditions. Drugs that specifically target the P2X1 receptor have been challenging to develop, and only recently have small molecule antagonists of the P2X1 receptor been available. However, these ligands need further biological validation for appropriate selectivity and drug-like properties before they will be suitable for use in preclinical models of disease. Although the atomic structure of the P2X1 receptor has yet to be determined, the recent discovery of several other P2X receptor structures and improvements in the field of structural biology suggests that this is now a distinct possibility. Such efforts may significantly improve drug discovery efforts at the P2X1 receptor.

Untangling Macropore Formation and Current Facilitation in P2X7

“…Since the intracellularly located C-terminus is significant for P2X7, these initial structures provided limited information about its cytoplasmic domain. Notably, P2X7 possesses a unique and unusually large C-terminus that is not present in other determined or predicted P2X structures [ 33 ]. Importantly, this C-terminus plays a crucial role in initiating apoptosis [ 22 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

High-throughput assessment identifying major platelet Ca2+ entry pathways via tyrosine kinase-linked and G protein-coupled receptors

“…As a most specific antagonist of ATP-induced Ca 2+ entry via P2× 1 channels, we tested MRS-2159 [55,56]. Furthemore, for blockage of the NCX3 Na + /Ca 2+ exchanger, we used the compound ORM-10,103.…”

A comprehensive review of the ten main platelet receptors involved in platelet activity and cardiovascular disease

“…The P2X 1 receptors have several subtypes (P2X 1 -P2X 7 ), numbered according to the chronological order of discovery. The exact mechanism by which this receptor works remains elusive, but P2X 1 knockout mice have displayed increased bleeding times and decreased thrombus formation, further indicating this receptor is of high importance [28,29].…”