NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers

Two classes of glutamate-activated channels mediate excitation at central synapses: N-methyl-d-aspartic acid (NMDA) receptors and non-NMDA receptors. Despite substantial structural homology, each class generates signals with characteristic kinetics and mediates distinct synaptic functions. In non-NM...

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Main Authors:	Borschel, William F, Murthy, Swetha E, Kasperek, Eileen M, Popescu, Gabriela K
Format:	Online
Language:	English
Published:	2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899702/

id	pubmed-3899702
recordtype	oai_dc
spelling	pubmed-38997022014-01-23 NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers Borschel, William F Murthy, Swetha E Kasperek, Eileen M Popescu, Gabriela K Article Two classes of glutamate-activated channels mediate excitation at central synapses: N-methyl-d-aspartic acid (NMDA) receptors and non-NMDA receptors. Despite substantial structural homology, each class generates signals with characteristic kinetics and mediates distinct synaptic functions. In non-NMDA receptors, the strength of inter-subunit contacts within agonist-binding domains is inversely correlated with functional desensitization. Here we test how the strength of these contacts affects NMDA receptor activation by combining mutagenesis and single-channel current analyses. We show that receptors with covalently linked dimers had dramatically lower activity due to high barriers to opening and unstable open states but had intact desensitization. Based on these observations, we suggest that in NMDA receptors rearrangements at the heterodimer interface represent an early and integral step of the opening sequence but are not required for desensitization. These results demonstrate distinct functional roles in the activation of NMDA and non-NMDA glutamate-gated channels for largely conserved inter-subunit contacts. 2011-10-11 /pmc/articles/PMC3899702/ /pubmed/21988914 http://dx.doi.org/10.1038/ncomms1512 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Borschel, William F Murthy, Swetha E Kasperek, Eileen M Popescu, Gabriela K
spellingShingle	Borschel, William F Murthy, Swetha E Kasperek, Eileen M Popescu, Gabriela K NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers
author_facet	Borschel, William F Murthy, Swetha E Kasperek, Eileen M Popescu, Gabriela K
author_sort	Borschel, William F
title	NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers
title_short	NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers
title_full	NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers
title_fullStr	NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers
title_full_unstemmed	NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers
title_sort	nmda receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers
description	Two classes of glutamate-activated channels mediate excitation at central synapses: N-methyl-d-aspartic acid (NMDA) receptors and non-NMDA receptors. Despite substantial structural homology, each class generates signals with characteristic kinetics and mediates distinct synaptic functions. In non-NMDA receptors, the strength of inter-subunit contacts within agonist-binding domains is inversely correlated with functional desensitization. Here we test how the strength of these contacts affects NMDA receptor activation by combining mutagenesis and single-channel current analyses. We show that receptors with covalently linked dimers had dramatically lower activity due to high barriers to opening and unstable open states but had intact desensitization. Based on these observations, we suggest that in NMDA receptors rearrangements at the heterodimer interface represent an early and integral step of the opening sequence but are not required for desensitization. These results demonstrate distinct functional roles in the activation of NMDA and non-NMDA glutamate-gated channels for largely conserved inter-subunit contacts.
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899702/
_version_	1612050460823257088

NMDA receptor activation requires remodeling of inter-subunit contacts within ligand-binding heterodimers

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