King, Brian F;
(2022)
Rehabilitation of the P2X5 receptor: a re-evaluation of structure and function.
Purinergic Signalling
10.1007/s11302-022-09903-0.
(In press).
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Abstract
Of the extended family of ATP-gated P2X ion-channels, the P2X5 receptor has received comparatively little attention since first cloned over 25 years ago. Disinterest in studying this P2X subtype stems from two commonly held beliefs: (i) canonical human P2X5 is non-functional because the P2X5 subunit is truncated (hP2X5A, 422 aa) and missing the critical peptide sequence (22 aa) encoded by exon 10; (ii) rat and mouse P2X5 subunits are fully formed (455 aa) but the receptor is only weakly functional, and successive ATP responses rapidly run down in amplitude. However, newer studies have re-evaluated these notions. First, a low proportion (around 10%) of humans possess full-length P2X5 subunits (444 aa) and can form competent P2X5 receptors. Full-length P2X5 has been identified only in black Americans, but may occur in a wider population as more ethnicities are screened. Second, replacement of one of three amino acids in rat P2X5 subunits with corresponding residues in human P2X5 subunits (V67I, S191F, or F195H) significantly improves the responsiveness of rat P2X5 to ATP. Replaced residues exert an allosteric action on the left flipper, allowing the docking jaw for ATP to flex the lower body of the subunit and fully open the ion pore. This proposed action may drive the search for naturally occurring modulators which act allosterically on wildtype rat P2X5. This review collates the available information on the structure and function of human and rat P2X5 receptors, with the view to rehabilitating the reputation of these ATP-gated ion channels and stimulating future lines of research.
| Type: | Article |
|---|---|
| Title: | Rehabilitation of the P2X5 receptor: a re-evaluation of structure and function |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s11302-022-09903-0 |
| Publisher version: | https://doi.org/10.1007/s11302-022-09903-0 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Neurosciences, Neurosciences & Neurology, P2X receptor, Ion channel, Purinergic, ATP, MOLECULAR-CLONING, P2X(5) RECEPTOR, ION-CHANNEL, EXPRESSION, IDENTIFICATION, ACTIVATION, SUBUNITS, DESENSITIZATION, PSEUDOGENES |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10164259 |
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