Purine and purinergic receptors

Abstract

Adenosine 5'-triphosphate acts as an extracellular signalling molecule (purinergic signalling), as well as an intracellular energy source. Adenosine 5'-triphosphate receptors have been cloned and characterised. P1 receptors are selective for adenosine, a breakdown product of adenosine 5'-triphosphate after degradation by ectonucleotidases. Four subtypes are recognised, A₁, A_2A, A_2B and A₃ receptors. P2 receptors are activated by purine and by pyrimidine nucleotides. P2X receptors are ligand-gated ion channel receptors (seven subunits (P2X1-7)), which form trimers as both homomultimers and heteromultimers. P2Y receptors are G protein-coupled receptors (eight subtypes (P2Y_{1/2/4/6/11/12/13/14})). There is both purinergic short-term signalling and long-term (trophic) signalling. The cloning of P2X-like receptors in primitive invertebrates suggests that adenosine 5'-triphosphate is an early evolutionary extracellular signalling molecule. Selective purinoceptor agonists and antagonists with therapeutic potential have been developed for a wide range of diseases, including thrombosis and stroke, dry eye, atherosclerosis, kidney failure, osteoporosis, bladder incontinence, colitis, neurodegenerative diseases and cancer.

Keywords: Adenosine 5′-triphosphate; P1 receptor; P2X receptor; P2Y receptor; adenosine.

Figure 1.

The architecture of the P2X4 receptor. Stereoview of the homotrimeric ΔzfP2X4 structure viewed parallel to the membrane. Each subunit is depicted in a different colour. N-acetylglucosamine (NAG) and glycosylated asparagine residues are shown in stick representation. The grey bars suggest the boundaries of the outer (out) and inner (in) leaflets of the membrane bilayer. Source: Reproduced from Kawate et al. (2009), with permission from the Nature Publishing Group.

Figure 2.

(a) Dendrogram to show relatedness of 29 P2X receptor subunits. Full-length amino acid sequences were aligned with Clustal W using default parameters. The dendrogram was constructed with TreeView. h, human (Homo sapiens); r, rat (Rattus norvegicus); m, mouse (Mus musculus); gp, guinea pig (Cavia porcellus); c, chicken (Gallus gallus); zf, zebrafish (Danio rerio); bf, bullfrog (Rana catesbeiana); x, claw-toed frog (Xenopus laevis); f, fugu (Takifugu rubripes). The ellipses indicate the apparent clustering by relatedness into subfamilies. Source: Reproduced from North (2002), with permission from the American Physiological Society. (b) A phylogenetic tree (dendrogram) showing the relationships among the current members of the P2Y receptor family (human P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁, P2Y₁₂ and P2Y₁₃ receptors) and the human UDP-glucose receptor (here indicated as the P2Y₁₄ receptor). The P2Y receptors can be divided into two subgroups shown with green and lilac backgrounds. Sequences were aligned using CLUSTALX and the tree was built using the TREEVIEW software. Source: Reproduced from Abbracchio et al. (2003), with permission from Elsevier.