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Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions
AMPA and NMDA receptors are ligand-gated ion channels that depolarize postsynaptic neurons when activated by the neurotransmitter L-glutamate. Changes in the distribution and activity of these receptors underlie learning and memory, but excessive change is associated with an array of neurological di...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Rockefeller University Press
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335009/ https://www.ncbi.nlm.nih.gov/pubmed/32342094 http://dx.doi.org/10.1085/jgp.201912537 |
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author | Wilding, Timothy J. Huettner, James E. |
author_facet | Wilding, Timothy J. Huettner, James E. |
author_sort | Wilding, Timothy J. |
collection | PubMed |
description | AMPA and NMDA receptors are ligand-gated ion channels that depolarize postsynaptic neurons when activated by the neurotransmitter L-glutamate. Changes in the distribution and activity of these receptors underlie learning and memory, but excessive change is associated with an array of neurological disorders, including cognitive impairment, developmental delay, and epilepsy. All of the ionotropic glutamate receptors (iGluRs) exhibit similar tetrameric architecture, transmembrane topology, and basic framework for activation; conformational changes induced by extracellular agonist binding deform and splay open the inner helix bundle crossing that occludes ion flux through the channel. NMDA receptors require agonist binding to all four subunits, whereas AMPA and closely related kainate receptors can open with less than complete occupancy. In addition to conventional activation by agonist binding, we recently identified two locations along the inner helix of the GluK2 kainate receptor subunit where cysteine (Cys) substitution yields channels that are opened by exposure to cadmium ions, independent of agonist site occupancy. Here, we generate AMPA and NMDA receptor subunits with homologous Cys substitutions and demonstrate similar activation of the mutant receptors by Cd. Coexpression of the auxiliary subunit stargazin enhanced Cd potency for activation of Cys-substituted GluA1 and altered occlusion upon treatment with sulfhydryl-reactive MTS reagents. Mutant NMDA receptors displayed voltage-dependent Mg block of currents activated by agonist and/or Cd as well as asymmetry between Cd effects on Cys-substituted GluN1 versus GluN2 subunits. In addition, Cd activation of each Cys-substituted iGluR was inhibited by protons. These results, together with our earlier work on GluK2, reveal a novel mechanism shared among the three different iGluR subtypes for prying open the gate that controls ion entry into the pore. |
format | Online Article Text |
id | pubmed-7335009 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-73350092021-01-06 Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions Wilding, Timothy J. Huettner, James E. J Gen Physiol Article AMPA and NMDA receptors are ligand-gated ion channels that depolarize postsynaptic neurons when activated by the neurotransmitter L-glutamate. Changes in the distribution and activity of these receptors underlie learning and memory, but excessive change is associated with an array of neurological disorders, including cognitive impairment, developmental delay, and epilepsy. All of the ionotropic glutamate receptors (iGluRs) exhibit similar tetrameric architecture, transmembrane topology, and basic framework for activation; conformational changes induced by extracellular agonist binding deform and splay open the inner helix bundle crossing that occludes ion flux through the channel. NMDA receptors require agonist binding to all four subunits, whereas AMPA and closely related kainate receptors can open with less than complete occupancy. In addition to conventional activation by agonist binding, we recently identified two locations along the inner helix of the GluK2 kainate receptor subunit where cysteine (Cys) substitution yields channels that are opened by exposure to cadmium ions, independent of agonist site occupancy. Here, we generate AMPA and NMDA receptor subunits with homologous Cys substitutions and demonstrate similar activation of the mutant receptors by Cd. Coexpression of the auxiliary subunit stargazin enhanced Cd potency for activation of Cys-substituted GluA1 and altered occlusion upon treatment with sulfhydryl-reactive MTS reagents. Mutant NMDA receptors displayed voltage-dependent Mg block of currents activated by agonist and/or Cd as well as asymmetry between Cd effects on Cys-substituted GluN1 versus GluN2 subunits. In addition, Cd activation of each Cys-substituted iGluR was inhibited by protons. These results, together with our earlier work on GluK2, reveal a novel mechanism shared among the three different iGluR subtypes for prying open the gate that controls ion entry into the pore. Rockefeller University Press 2020-04-27 /pmc/articles/PMC7335009/ /pubmed/32342094 http://dx.doi.org/10.1085/jgp.201912537 Text en © 2020 Wilding and Huettner http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Wilding, Timothy J. Huettner, James E. Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions |
title | Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions |
title_full | Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions |
title_fullStr | Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions |
title_full_unstemmed | Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions |
title_short | Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions |
title_sort | cadmium activates ampa and nmda receptors with m3 helix cysteine substitutions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335009/ https://www.ncbi.nlm.nih.gov/pubmed/32342094 http://dx.doi.org/10.1085/jgp.201912537 |
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