Hodgkin-Huxley-Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif

Perszyk, R. E., Myers, S. J., Yuan, H., Gibb, A. J., Furukawa, H., Sobolevsky, A. I., Traynelis, S. F. (August 2020) Hodgkin-Huxley-Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif. J Physiol, 598 (15). pp. 3071-3083. ISSN 0022-3751

URL: https://pubmed.ncbi.nlm.nih.gov/32468591/
DOI: 10.1113/jp278086

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.

Item Type: Paper
Additional Information: 1469-7793 Perszyk, Riley E Orcid: 0000-0001-8283-7709 Myers, Scott J Orcid: 0000-0002-6689-3978 Yuan, Hongjie Orcid: 0000-0002-8127-7145 Gibb, Alasdair J Orcid: 0000-0002-2145-1615 Furukawa, Hiro Orcid: 0000-0001-8296-8426 Sobolevsky, Alexander I Orcid: 0000-0001-5181-8644 Traynelis, Stephen F Orcid: 0000-0002-3750-9615 R01 NS083660/GF/NIH HHS/United States #00085889/University Research Committee/ R01 HD082373/HD/NICHD NIH HHS/United States 1818213/Division of Molecular and Cellular Biosciences/ MH085926/MH/NIMH NIH HHS/United States R01 NS107253/GF/NIH HHS/United States NS111745/NS/NINDS NIH HHS/United States R01 CA206573/GF/NIH HHS/United States RO1 MH085926/GF/NIH HHS/United States R35 NS111619/GF/NIH HHS/United States R01 HD082373/GF/NIH HHS/United States HD082373/National Institute of Child Health and Human Development/ R01 NS111745/GF/NIH HHS/United States CA206573/CA/NCI NIH HHS/United States 1818213/nsf/ Journal Article England J Physiol. 2020 Aug;598(15):3071-3083. doi: 10.1113/JP278086. Epub 2020 Jun 15.
Uncontrolled Keywords: NMDA receptor allosteric modulators channel gating genetics human variants ionotropic glutamate receptors structural biology
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Matthew Dunn
Date: August 2020
Date Deposited: 19 Feb 2021 19:46
Last Modified: 25 Jun 2021 13:30
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39875

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