eprintid: 10099359 rev_number: 18 eprint_status: archive userid: 608 dir: disk0/10/09/93/59 datestamp: 2020-06-03 08:24:37 lastmod: 2021-09-19 23:54:19 status_changed: 2020-06-03 08:24:37 type: article metadata_visibility: show creators_name: Perszyk, RE creators_name: Myers, SJ creators_name: Yuan, H creators_name: Gibb, AJ creators_name: Furukawa, H creators_name: Sobolevsky, AI creators_name: Traynelis, SF title: Hodgkin–Huxley–Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D09 divisions: G02 keywords: NMDA receptor, allosteric modulators, channel gating, genetics, human variants, ionotropic glutamate receptors, structural biology note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. abstract: Glutamate receptors are essential ligand-gated ion channels in the central nervous system that mediate excitatory synaptic transmission in response to the release of glutamate from presynaptic terminals. The structural and biophysical basis underlying the function of these receptors has been studied for decades by a wide range of approaches. However recent structural, pharmacological, and genetic studies have provided new insight into the regions of this protein that are critical determinants of receptor function. Lack of variation in specific areas of the protein amino acid sequences in the human population has defined three regions in each receptor subunit that are under selective pressure, which has focused research efforts and driven new hypotheses. In addition, these three closely positioned elements reside near a cavity that is shown by multiple studies to be a likely site of action for allosteric modulators, one of which is currently in use as an FDA-approved anticonvulsant. These structural elements are capable of controlling gating of the pore, and appear to permit some modulators bound within the cavity to also alter permeation properties. This creates a new precedent whereby features of the channel pore can be modulated by exogenous drugs that bind outside the pore. The convergence of structural, genetic, biophysical, and pharmacological approaches is a powerful means to gain insight into the complex biological processes defined by neurotransmitter receptor function. This article is protected by copyright. All rights reserved. date: 2020-08-01 date_type: published official_url: http://dx.doi.org/10.1113/JP278086 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1786844 doi: 10.1113/JP278086 lyricists_name: Gibb, Alasdair lyricists_id: AJGIB07 actors_name: Gibb, Alasdair actors_id: AJGIB07 actors_role: owner full_text_status: public publication: The Journal of Physiology volume: 598 number: 15 pagerange: 3071-3083 event_location: England citation: Perszyk, RE; Myers, SJ; Yuan, H; Gibb, AJ; Furukawa, H; Sobolevsky, AI; Traynelis, SF; (2020) Hodgkin–Huxley–Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif. The Journal of Physiology , 598 (15) pp. 3071-3083. 10.1113/JP278086 <https://doi.org/10.1113/JP278086>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10099359/1/Perszyk-Hodgkin-Huxley-Katz-Prize-Lecture-J-Physiol-2020-JP278086.pdf