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Unprecedented structural insights: NMDA receptors can be blocked to limit neurotoxicity
Date:1/22/2014

Cold Spring Harbor, NY Structural biologists at Cold Spring Harbor Laboratory (CSHL) and collaborators at Emory University have obtained important scientific results likely to advance efforts to develop new drugs targeting NMDA receptors in the brain.

NMDA (N-methyl D-aspartate) receptors are found on the surface of many nerve cells and are involved in signaling that is essential in basic brain functions including learning and memory formation. Problems with their function have been implicated in depression, schizophrenia, Alzheimer's and Parkinson's diseases, as well as brain damage caused by stroke.

Normally, NMDA receptors are activated by glutamate, the most common neurotransmitter of excitatory cell-to-cell messages in the brain.

Overactivation of NMDA receptors is a known cause of nerve-cell toxicity. Thus, drug developers have long sought compounds that can selectively block or antagonize NMDA receptors, while not affecting other types of glutamate receptors in the brain, whose function is essential. However, a basic question -- how those compounds bind and antagonize NMDA receptors -- has not been understood at the molecular level.

Over a period of years, CSHL Associate Professor Hiro Furukawa and colleagues have taken a step-by-step approach to learn about the precise shape of various subunits of the complex NMDA receptor protein, and demonstrating the relationship between different versions of the receptor's shape and its function. (see more here) Since the subunits have different biological roles, they have to be specifically targeted by drug compounds to obtain specific effects.

Furukawa's team has used a technique called x-ray crystallography to map various domains of the protein while it is bound to different chemical compounds, or antagonists, that downregulate its function. Today in the journal Neuron they publish the first crystal structures of two NMDA receptor subunits (called GluN1
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Contact: Peter Tarr
tarr@cshl.edu
516-367-8455
Cold Spring Harbor Laboratory
Source:Eurekalert  

Page: 1 2

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Unprecedented structural insights: NMDA receptors can be blocked to limit neurotoxicity
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