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.

Keywords: ATP; Bladder dysfunction; Drug discovery; Male contraception; Structural biology; Thrombosis and inflammation.

Fig. 1

a A monomeric subunit of the P2X receptor in the plasma membrane and b a functional trimeric P2X receptor shown as a cartoon. There are three ATP binding sites located in the extracellular domain between subunits. Upon receptor activation by ATP binding, there is an inward flux of calcium and sodium ions and an outward flux of potassium ions

Fig. 2

Chemical structures of P2X1 receptor modulators. P2X1 receptor modulators are referred to by their most common abbreviated name except for compounds 1–5 which do not have a common name and have been assigned a number

Fig. 3

a Experimentally determined P2X structures coloured by features of a dolphin (based on the zfP2X4 [10]) with the head domain in pink, the upper body in dark blue, the lower body in light blue, the left flipper in yellow, the right flipper in red, the dorsal fin in orange and the fluke in green. b AlphaFold generated P2X receptor structures with each residue coloured by the confidence of the prediction with dark blue a very high confidence prediction, light blue a high confidence prediction, yellow a low confidence prediction and orange a very low confidence prediction

Fig. 4

a ATP-bound hP2X3 receptor with one of the ATP binding locations emphasised (Protein Data Bank: 5SVK). b A close up view of the ATP molecule bound to the hP2X3 receptor with the interacting residues labelled, the interacting hP2X3 residues are reported in the table below with the sequence aligned P2X1 residues