Role of cross-cleft contacts in NMDA receptor gating.

In response to brief glutamate exposure, NMDA receptors produce excitatory currents that have sub-maximal amplitudes and characteristically slow kinetics. The activation sequence starts when glutamate binds to residues located on the upper lobe of extracellularly located ligand-binding domains (LBDs...

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Autores principales:	Meaghan A Paganelli, Cassandra L Kussius, Gabriela K Popescu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/32838e0657084d0e85616958e8679ebc
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spelling	oai:doaj.org-article:32838e0657084d0e85616958e8679ebc2021-11-18T08:45:11ZRole of cross-cleft contacts in NMDA receptor gating.1932-620310.1371/journal.pone.0080953https://doaj.org/article/32838e0657084d0e85616958e8679ebc2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24278352/?tool=EBIhttps://doaj.org/toc/1932-6203In response to brief glutamate exposure, NMDA receptors produce excitatory currents that have sub-maximal amplitudes and characteristically slow kinetics. The activation sequence starts when glutamate binds to residues located on the upper lobe of extracellularly located ligand-binding domains (LBDs) and then contacts lower lobe residues to bridge the cleft between the two hinged lobes. This event stabilizes a narrow-cleft LBD conformation and may facilitate subsequent inter-lobe contacts that further stabilize the closed cleft. Agonist efficacy has been traced to the degree of agonist-induced cleft-closure and may also depend on the stability of the closed-cleft conformation. To investigate how cross-cleft contacts contribute to the amplitude and kinetics of NMDA receptor response, we examined the activation reaction of GluN1/GluN2A receptors that had single-residue substitutions at the interface between LBD lobes. We found that side-chain truncations at residues of putative contact between lobes increased glutamate efficacy through independent additive mechanisms in GluN1 and GluN2A subunits. In contrast, removing side-chain charge with isosteric substitutions at the same sites decreased glutamate efficacy. These results support the view that in GluN1/GluN2A receptors' natural interactions between residues on opposing sides of the ligand-binding cleft encode the stability of the glutamate-bound closed-cleft conformations and limit the degree of cleft closure, thus contributing to the sub-maximal response and emblematically slow NMDA receptor deactivation after brief stimulation.Meaghan A PaganelliCassandra L KussiusGabriela K PopescuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e80953 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Meaghan A Paganelli Cassandra L Kussius Gabriela K Popescu Role of cross-cleft contacts in NMDA receptor gating.
description	In response to brief glutamate exposure, NMDA receptors produce excitatory currents that have sub-maximal amplitudes and characteristically slow kinetics. The activation sequence starts when glutamate binds to residues located on the upper lobe of extracellularly located ligand-binding domains (LBDs) and then contacts lower lobe residues to bridge the cleft between the two hinged lobes. This event stabilizes a narrow-cleft LBD conformation and may facilitate subsequent inter-lobe contacts that further stabilize the closed cleft. Agonist efficacy has been traced to the degree of agonist-induced cleft-closure and may also depend on the stability of the closed-cleft conformation. To investigate how cross-cleft contacts contribute to the amplitude and kinetics of NMDA receptor response, we examined the activation reaction of GluN1/GluN2A receptors that had single-residue substitutions at the interface between LBD lobes. We found that side-chain truncations at residues of putative contact between lobes increased glutamate efficacy through independent additive mechanisms in GluN1 and GluN2A subunits. In contrast, removing side-chain charge with isosteric substitutions at the same sites decreased glutamate efficacy. These results support the view that in GluN1/GluN2A receptors' natural interactions between residues on opposing sides of the ligand-binding cleft encode the stability of the glutamate-bound closed-cleft conformations and limit the degree of cleft closure, thus contributing to the sub-maximal response and emblematically slow NMDA receptor deactivation after brief stimulation.
format	article
author	Meaghan A Paganelli Cassandra L Kussius Gabriela K Popescu
author_facet	Meaghan A Paganelli Cassandra L Kussius Gabriela K Popescu
author_sort	Meaghan A Paganelli
title	Role of cross-cleft contacts in NMDA receptor gating.
title_short	Role of cross-cleft contacts in NMDA receptor gating.
title_full	Role of cross-cleft contacts in NMDA receptor gating.
title_fullStr	Role of cross-cleft contacts in NMDA receptor gating.
title_full_unstemmed	Role of cross-cleft contacts in NMDA receptor gating.
title_sort	role of cross-cleft contacts in nmda receptor gating.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/32838e0657084d0e85616958e8679ebc
work_keys_str_mv	AT meaghanapaganelli roleofcrosscleftcontactsinnmdareceptorgating AT cassandralkussius roleofcrosscleftcontactsinnmdareceptorgating AT gabrielakpopescu roleofcrosscleftcontactsinnmdareceptorgating
_version_	1718421373922050048

Role of cross-cleft contacts in NMDA receptor gating.

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