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Title: Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Abstract

Recent genome projects for ctenophores have revealed the presence of numerous ionotropic glutamate receptors (iGluRs) in Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest metazoan ancestors. Sequence alignments and phylogenetic analysis show that these form a distinct clade from the well-characterized AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. Although annotated as glutamate and kainate receptors, crystal structures of the ML032222a and PbiGluR3 ligand-binding domains (LBDs) reveal endogenous glycine in the binding pocket, whereas ligand-binding assays show that glycine binds with nanomolar affinity; biochemical assays and structural analysis establish that glutamate is occluded from the binding cavity. Further analysis reveals ctenophore-specific features, such as an interdomain Arg-Glu salt bridge, present only in subunits that bind glycine, but also a conserved disulfide in loop 1 of the LBD that is found in all vertebrate NMDA but not AMPA or kainate receptors. In this paper, we hypothesize that ctenophore iGluRs are related to an early ancestor of NMDA receptors, suggesting a common evolutionary path for ctenophores and bilaterian species, and finally suggest that future work should consider both glycine and glutamate as candidate neurotransmitters in ctenophore species.

Authors:
 [1];  [1];  [1];  [2];  [1]
  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Child Health and Human Development. Lab. of Cellular and Molecular Neurophysiology
  2. Univ. of Florida, St. Augustine, FL (United States). The Whitney Lab. for Marine Bioscience
Publication Date:
Research Org.:
National Institutes of Health (NIH), Bethesda, MD (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health (NIH) (United States); National Aeronautics and Space Administration (NASA)
Contributing Org.:
Univ. of Florida, St. Augustine, FL (United States)
OSTI Identifier:
1228098
Grant/Contract Number:  
W-31-109-Eng-38; 00093371
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 112; Journal Issue: 44; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; NMDA receptors; ctenophores; crystal structures; evolution

Citation Formats

Alberstein, Robert, Grey, Richard, Zimmet, Austin, Simmons, David K., and Mayer, Mark L. Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes. United States: N. p., 2015. Web. doi:10.1073/pnas.1513771112.
Alberstein, Robert, Grey, Richard, Zimmet, Austin, Simmons, David K., & Mayer, Mark L. Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes. United States. https://doi.org/10.1073/pnas.1513771112
Alberstein, Robert, Grey, Richard, Zimmet, Austin, Simmons, David K., and Mayer, Mark L. Mon . "Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes". United States. https://doi.org/10.1073/pnas.1513771112. https://www.osti.gov/servlets/purl/1228098.
@article{osti_1228098,
title = {Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes},
author = {Alberstein, Robert and Grey, Richard and Zimmet, Austin and Simmons, David K. and Mayer, Mark L.},
abstractNote = {Recent genome projects for ctenophores have revealed the presence of numerous ionotropic glutamate receptors (iGluRs) in Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest metazoan ancestors. Sequence alignments and phylogenetic analysis show that these form a distinct clade from the well-characterized AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. Although annotated as glutamate and kainate receptors, crystal structures of the ML032222a and PbiGluR3 ligand-binding domains (LBDs) reveal endogenous glycine in the binding pocket, whereas ligand-binding assays show that glycine binds with nanomolar affinity; biochemical assays and structural analysis establish that glutamate is occluded from the binding cavity. Further analysis reveals ctenophore-specific features, such as an interdomain Arg-Glu salt bridge, present only in subunits that bind glycine, but also a conserved disulfide in loop 1 of the LBD that is found in all vertebrate NMDA but not AMPA or kainate receptors. In this paper, we hypothesize that ctenophore iGluRs are related to an early ancestor of NMDA receptors, suggesting a common evolutionary path for ctenophores and bilaterian species, and finally suggest that future work should consider both glycine and glutamate as candidate neurotransmitters in ctenophore species.},
doi = {10.1073/pnas.1513771112},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 44,
volume = 112,
place = {United States},
year = {Mon Oct 12 00:00:00 EDT 2015},
month = {Mon Oct 12 00:00:00 EDT 2015}
}

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Works referenced in this record:

Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain
journal, March 2013

  • Schauder, D. M.; Kuybeda, O.; Zhang, J.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 15
  • DOI: 10.1073/pnas.1217549110

Structure and Mechanism of Kainate Receptor Modulation by Anions
journal, March 2007


Crystal structure and association behaviour of the GluR2 amino-terminal domain
journal, May 2009

  • Jin, Rongsheng; Singh, Satinder K.; Gu, Shenyan
  • The EMBO Journal, Vol. 28, Issue 12
  • DOI: 10.1038/emboj.2009.140

Very fast empirical prediction and rationalization of protein pKa values
journal, October 2005

  • Li, Hui; Robertson, Andrew D.; Jensen, Jan H.
  • Proteins: Structure, Function, and Bioinformatics, Vol. 61, Issue 4
  • DOI: 10.1002/prot.20660

Overview of the CCP 4 suite and current developments
journal, March 2011

  • Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S0907444910045749

Structural mechanism of glutamate receptor activation and desensitization
journal, August 2014

  • Meyerson, Joel R.; Kumar, Janesh; Chittori, Sagar
  • Nature, Vol. 514, Issue 7522
  • DOI: 10.1038/nature13603

Evolutionary Profiles Derived from the QR Factorization of Multiple Structural Alignments Gives an Economy of Information
journal, February 2005


Zinc Potentiates GluK3 Glutamate Receptor Function by Stabilizing the Ligand Binding Domain Dimer Interface
journal, November 2012


RNA editing in brain controls a determinant of ion flow in glutamate-gated channels
journal, October 1991


The ctenophore genome and the evolutionary origins of neural systems
journal, May 2014

  • Moroz, Leonid L.; Kocot, Kevin M.; Citarella, Mathew R.
  • Nature, Vol. 510, Issue 7503
  • DOI: 10.1038/nature13400

Anions Mediate Ligand Binding in Adineta vaga Glutamate Receptor Ion Channels
journal, March 2013


An Improved General Amino Acid Replacement Matrix
journal, April 2008


Functional characterization of a potassium-selective prokaryotic glutamate receptor
journal, December 1999

  • Chen, Guo-Qiang; Cui, Changhai; Mayer, Mark L.
  • Nature, Vol. 402, Issue 6763
  • DOI: 10.1038/45568

Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor.
journal, November 1990


SignalP 4.0: discriminating signal peptides from transmembrane regions
journal, September 2011

  • Petersen, Thomas Nordahl; Brunak, Søren; von Heijne, Gunnar
  • Nature Methods, Vol. 8, Issue 10
  • DOI: 10.1038/nmeth.1701

Energetics of glutamate receptor ligand binding domain dimer assembly are modulated by allosteric ions
journal, July 2009

  • Chaudhry, C.; Plested, A. J. R.; Schuck, P.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 30
  • DOI: 10.1073/pnas.0904175106

SEDPHAT – A platform for global ITC analysis and global multi-method analysis of molecular interactions
journal, April 2015


Ancient Protostome Origin of Chemosensory Ionotropic Glutamate Receptors and the Evolution of Insect Taste and Olfaction
journal, August 2010


X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor
journal, November 2009

  • Sobolevsky, Alexander I.; Rosconi, Michael P.; Gouaux, Eric
  • Nature, Vol. 462, Issue 7274
  • DOI: 10.1038/nature08624

Measuring substrate binding and affinity of purified membrane transport proteins using the scintillation proximity assay
journal, August 2012


Glutamate receptors at atomic resolution
journal, March 2006


Molecular Basis of Kainate Receptor Modulation by Sodium
journal, June 2008


Mechanisms for ligand binding to GluR0 ion channels: crystal structures of the glutamate and serine complexes and a closed apo state
journal, August 2001

  • Mayer, Mark L.; Olson, Rich; Gouaux, Eric
  • Journal of Molecular Biology, Vol. 311, Issue 4
  • DOI: 10.1006/jmbi.2001.4884

Convergence of ion channel genome content in early animal evolution
journal, February 2015

  • Liebeskind, Benjamin J.; Hillis, David M.; Zakon, Harold H.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 8
  • DOI: 10.1073/pnas.1501195112

Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors
journal, July 2008

  • Yao, Yongneng; Harrison, Chris B.; Freddolino, Peter L.
  • The EMBO Journal, Vol. 27, Issue 15
  • DOI: 10.1038/emboj.2008.140

Concanavalin A blocks desensitisation of glutamate receptors on insect muscle fibres
journal, February 1976

  • Mathers, D. A.; Usherwood, P. N. R.
  • Nature, Vol. 259, Issue 5542
  • DOI: 10.1038/259409a0

Crystal structure of a heterotetrameric NMDA receptor ion channel
journal, May 2014


Amino acid substitutions in the pore of rat glutamate receptors at sites influencing block by polyamines
journal, October 1999


Glycine potentiates the NMDA response in cultured mouse brain neurons
journal, February 1987


Cloned Glutamate Receptors
journal, March 1994


Multiple effects of spermine on N-methyl-D-aspartic acid receptor responses of rat cultured hippocampal neurones.
journal, May 1993


NMDA receptor structures reveal subunit arrangement and pore architecture
journal, June 2014

  • Lee, Chia-Hsueh; Lü, Wei; Michel, Jennifer Carlisle
  • Nature, Vol. 511, Issue 7508
  • DOI: 10.1038/nature13548

Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones
journal, May 1984

  • Mayer, Mark L.; Westbrook, Gary L.; Guthrie, Peter B.
  • Nature, Vol. 309, Issue 5965
  • DOI: 10.1038/309261a0

Conformational restriction blocks glutamate receptor desensitization
journal, November 2006

  • Weston, Matthew C.; Schuck, Peter; Ghosal, Alokesh
  • Nature Structural & Molecular Biology, Vol. 13, Issue 12
  • DOI: 10.1038/nsmb1178

The Trichoplax genome and the nature of placozoans
journal, August 2008

  • Srivastava, Mansi; Begovic, Emina; Chapman, Jarrod
  • Nature, Vol. 454, Issue 7207
  • DOI: 10.1038/nature07191

Excitatory Amino Acid Transmitters
journal, April 1981


The N-terminal domain of GluR6-subtype glutamate receptor ion channels
journal, May 2009

  • Kumar, Janesh; Schuck, Peter; Jin, Rongsheng
  • Nature Structural & Molecular Biology, Vol. 16, Issue 6
  • DOI: 10.1038/nsmb.1613

Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins
journal, December 1994


Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A
journal, December 1993


Structural Similarities between Glutamate Receptor Channels and K+ Channels Examined by Scanning Mutagenesis
journal, March 2001

  • Panchenko, Victor A.; Glasser, Carla R.; Mayer, Mark L.
  • The Journal of General Physiology, Vol. 117, Issue 4
  • DOI: 10.1085/jgp.117.4.345

Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

A modern ionotropic glutamate receptor with a K+ selectivity signature sequence
journal, March 2011

  • Janovjak, H.; Sandoz, G.; Isacoff, E. Y.
  • Nature Communications, Vol. 2, Issue 1
  • DOI: 10.1038/ncomms1231

Novel Cell Types, Neurosecretory Cells, and Body Plan of the Early-Diverging Metazoan Trichoplax adhaerens
journal, July 2014

  • Smith, Carolyn L.; Varoqueaux, Frédérique; Kittelmann, Maike
  • Current Biology, Vol. 24, Issue 14
  • DOI: 10.1016/j.cub.2014.05.046

Subunit arrangement and function in NMDA receptors
journal, November 2005

  • Furukawa, Hiroyasu; Singh, Satinder K.; Mancusso, Romina
  • Nature, Vol. 438, Issue 7065
  • DOI: 10.1038/nature04089

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

The Genome of the Ctenophore Mnemiopsis leidyi and Its Implications for Cell Type Evolution
journal, December 2013


Magnesium gates glutamate-activated channels in mouse central neurones
journal, February 1984

  • Nowak, L.; Bregestovski, P.; Ascher, P.
  • Nature, Vol. 307, Issue 5950
  • DOI: 10.1038/307462a0

Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes
journal, August 1988


Functional reconstitution of Drosophila melanogaster NMJ glutamate receptors
journal, April 2015

  • Han, Tae Hee; Dharkar, Poorva; Mayer, Mark L.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 19
  • DOI: 10.1073/pnas.1500458112

NMRPipe: A multidimensional spectral processing system based on UNIX pipes
journal, November 1995

  • Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW.
  • Journal of Biomolecular NMR, Vol. 6, Issue 3
  • DOI: 10.1007/BF00197809

Detection of L -lactate in polyethylene glycol solutions confirms the identity of the active-site ligand in a proline dehydrogenase structure
journal, April 2004

  • Zhang, Min; Tanner, John J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 5
  • DOI: 10.1107/S0907444904003786

MUSTANG: A multiple structural alignment algorithm
journal, May 2006

  • Konagurthu, Arun S.; Whisstock, James C.; Stuckey, Peter J.
  • Proteins: Structure, Function, and Bioinformatics, Vol. 64, Issue 3
  • DOI: 10.1002/prot.20921

Modulation of the Dimer Interface at Ionotropic Glutamate-Like Receptor  2 by D-Serine and Extracellular Calcium
journal, January 2009


A kinetic analysis of the modulation of N-methyl-D-aspartic acid receptors by glycine in mouse cultured hippocampal neurones.
journal, September 1990


Structure and Dynamics of AMPA Receptor GluA2 in Resting, Pre-Open, and Desensitized States
journal, August 2014


VMD: Visual molecular dynamics
journal, February 1996


Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

The composition of Standard Seawater and the definition of the Reference-Composition Salinity Scale
journal, January 2008

  • Millero, Frank J.; Feistel, Rainer; Wright, Daniel G.
  • Deep Sea Research Part I: Oceanographic Research Papers, Vol. 55, Issue 1
  • DOI: 10.1016/j.dsr.2007.10.001

[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997


Works referencing / citing this record:

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journal, July 2020


Family matters
journal, August 2013

  • Hudson, Kathy L.; Collins, Francis S.
  • Nature, Vol. 500, Issue 7461
  • DOI: 10.1038/500141a

Metazoan evolution of glutamate receptors reveals unreported phylogenetic groups and divergent lineage-specific events
journal, November 2018

  • Ramos-Vicente, David; Ji, Jie; Gratacòs-Batlle, Esther
  • eLife, Vol. 7
  • DOI: 10.7554/elife.35774

Structural mechanisms of activation and desensitization in neurotransmitter-gated ion channels
journal, June 2016

  • Plested, Andrew J. R.
  • Nature Structural & Molecular Biology, Vol. 23, Issue 6
  • DOI: 10.1038/nsmb.3214

Family Matters
journal, January 2018


The genome of the contractile demosponge Tethya wilhelma and the evolution of metazoan neural signalling pathways
posted_content, April 2017

  • Francis, Warren R.; Eitel, Michael; Vargas, Sergio
  • bioRxiv
  • DOI: 10.1101/120998

Chemosensory adaptations of the mountain fly Drosophila nigrosparsa (Insecta: Diptera) through genomics’ and structural biology’s lenses
journal, March 2017

  • Cicconardi, Francesco; Di Marino, Daniele; Olimpieri, Pier Paolo
  • Scientific Reports, Vol. 7, Issue 1
  • DOI: 10.1038/srep43770

‘Family matters’: Ageing and the intergenerational social contract in urban Ahmedabad, Gujarat
journal, September 2017

  • Gangopadhyay, Jagriti; Samanta, Tannistha
  • Contributions to Indian Sociology, Vol. 51, Issue 3
  • DOI: 10.1177/0069966717720962

The structural bases for agonist diversity in an Arabidopsis thaliana glutamate receptor-like channel
journal, December 2019

  • Alfieri, Andrea; Doccula, Fabrizio G.; Pederzoli, Riccardo
  • Proceedings of the National Academy of Sciences, Vol. 117, Issue 1
  • DOI: 10.1073/pnas.1905142117

Neto-α controls synapse organization and homeostasis at the Drosophila neuromuscular junction
posted_content, October 2019

  • Han, Tae Hee; Vicidomini, Rosario; Ramos, Cathy Isaura
  • Cell Reports
  • DOI: 10.1101/812040

Family Matters: Family Quality of Life in Dementia
journal, June 2011


Family matters
journal, December 2018


The genome of the contractile demosponge Tethya wilhelma and the evolution of metazoan neural signalling pathways
posted_content, April 2017

  • Francis, Warren R.; Eitel, Michael; Vargas, Sergio
  • bioRxiv
  • DOI: 10.1101/120998

Neuropeptidergic integration of behavior in Trichoplax adhaerens, an animal without synapses
journal, September 2017

  • Senatore, Adriano; Reese, Thomas S.; Smith, Carolyn L.
  • Journal of Experimental Biology, Vol. 220, Issue 18
  • DOI: 10.1242/jeb.162396

Metazoan evolution of glutamate receptors reveals unreported phylogenetic groups and divergent lineage-specific events
journal, November 2018

  • Ramos-Vicente, David; Ji, Jie; Gratacòs-Batlle, Esther
  • eLife, Vol. 7
  • DOI: 10.7554/elife.35774

Family matters
journal, December 2018