Structural Insights into Allosteric Modulation of NMDA Receptors Through the Amino-Terminal Domain

Karakas, Erkan, Simorowski, Noriko, Furukawa, Hiro (January 2010) Structural Insights into Allosteric Modulation of NMDA Receptors Through the Amino-Terminal Domain. Biophysical Journal, 98 (3, Sup). 609a-609a.

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Abstract

Majority of fast excitatory synaptic transmission in the mammalian brain is mediated by a class of molecules called ionotropic glutamate receptors, which include N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are hetero-tetrameric ion channels that are composed of two NR1 subunits and two NR2 (A-D) subunits or NR3 subunits. NMDA receptors play key roles in numbers of important processes including synaptic plasticity and development in normal state, whereas aberrant activity of NMDA receptors is associated with ischemic brain injury and neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. Activity of NMDA receptor is tightly controlled through multiple pathways. One such mechanism is allosteric modulation through binding of small molecules to the extracellular amino terminal domain (ATD) in a subtype specific manner, i.e. polyamines and protons bind NR1, Zn2+ binds both NR2A and NR2B, and phenylethanolamine compounds bind NR2B. To understand the molecular mechanism of the ATD-dependent allosteric modulation of NMDA receptors, we have solved the structures of NR2B ATD in the zinc-bound and -free forms. The structures reveal an overall clamshell architecture with a unique domain orientation distinct from the non-NMDA receptor ATDs and molecular determinants for the zinc binding site, ion binding sites, and the architecture of the putative phenylethanolamine binding site.

Item Type: Paper
Additional Information: Meeting abstract
Subjects: diseases & disorders > mental disorders > delirium dementia cognitive disorders > Alzheimer's disease
diseases & disorders > nervous system diseases and disorders
Publication Type > Meeting Abstract
CSHL Authors:
Communities: CSHL Post Doctoral Fellows
CSHL labs > Furukawa lab
Depositing User: CSHL Librarian
Date: January 2010
Date Deposited: 30 Sep 2011 20:26
Last Modified: 07 Mar 2018 18:55
URI: https://repository.cshl.edu/id/eprint/15445

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