+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Structural basis for the functional properties of the P2X7 receptor for extracellular ATP


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          The P2X7 receptor, originally known as the P2Z receptor due to its distinctive functional properties, has a structure characteristic of the ATP-gated ion channel P2X receptor family. The P2X7 receptor is an important mediator of ATP-induced purinergic signalling and is involved the pathogenesis of numerous conditions as well as in the regulation of diverse physiological functions. Functional characterisations, in conjunction with site-directed mutagenesis, molecular modelling, and, recently, structural determination, have provided significant insights into the structure–function relationships of the P2X7 receptor. This review discusses the current understanding of the structural basis for the functional properties of the P2X7 receptor.

          Related collections

          Most cited references79

          • Record: found
          • Abstract: found
          • Article: not found

          Crystal structure of the ATP-gated P2X4 ion channel in the closed state

          Summary P2X receptors are cation selective ion channels gated by extracellular ATP and implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is presently no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X4 receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in β-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. Within the transmembrane pore, the ‘gate’ is defined by an ~8 Ǻ slab of protein. We define the location of three non-canonical, intersubunit ATP binding sites and suggest that ATP binding promotes subunit rearrangement and ion channel opening.
            • Record: found
            • Abstract: found
            • Article: not found

            Molecular mechanism of ATP binding and ion channel activation in P2X receptors.

            P2X receptors are trimeric ATP-activated ion channels permeable to Na+, K+ and Ca2+. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body β-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents.
              • Record: found
              • Abstract: found
              • Article: not found

              The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease.

              The P2X7 receptor is a trimeric ATP-gated cation channel found predominantly, but not exclusively, on immune cells. P2X7 activation results in a number of downstream events, including the release of proinflammatory mediators and cell death and proliferation. As such, P2X7 plays important roles in various inflammatory, immune, neurologic and musculoskeletal disorders. This review focuses on the use of P2X7 antagonists in rodent models of neurologic disease and injury, inflammation, and musculoskeletal and other disorders. The cloning and characterization of human, rat, mouse, guinea pig, dog, and Rhesus macaque P2X7, as well as recent observations regarding the gating and permeability of P2X7, are discussed. Furthermore, this review discusses polymorphic and splice variants of P2X7, as well as the generation and use of P2X7 knockout mice. Recent evidence for emerging signaling pathways downstream of P2X7 activation and the growing list of negative and positive modulators of P2X7 activation and expression are also described. In addition, the use of P2X7 antagonists in numerous rodent models of disease is extensively summarized. Finally, the use of P2X7 antagonists in clinical trials in humans and future directions exploring P2X7 as a therapeutic target are described. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

                Author and article information

                Purinergic Signal
                Purinergic Signal
                Purinergic Signalling
                Springer Netherlands (Dordrecht )
                13 May 2021
                13 May 2021
                September 2021
                : 17
                : 3
                : 331-344
                [1 ]GRID grid.9909.9, ISNI 0000 0004 1936 8403, School of Biomedical Sciences, Faculty of Biological Sciences, , University of Leeds, ; Leeds, UK
                [2 ]GRID grid.443984.6, Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, , St James’s University Hospital, ; Leeds, UK
                [3 ]GRID grid.12366.30, ISNI 0000 0001 2182 6141, EA4245, Transplantation, Immunology and Inflammation, Faculty of Medicine, , University of Tours, ; Tours, France
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Review Article
                Custom metadata
                © Springer Nature B.V. 2021

                Cell biology
                agonist binding,receptor activation,ion permeation,large pore formation,antagonism
                Cell biology
                agonist binding, receptor activation, ion permeation, large pore formation, antagonism


                Comment on this article