Navigation Links
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 and GluN2A) in complex with four different compounds known to have the capacity to inhibit, or antagonize, NMDA receptor function.

Showing this two-unit ligand binding domain (LBD) in complex with NMDA antagonists -- potential drugs -- reveals that each antagonist has a distinctive mode of binding the LBD. In essence, the "docking port" is held open, but to a different extent when different antagonists are bound. The study also reveals an element in the antagonist binding site that is only present in GluN2A subunit, but not in the others. This previously hidden information, says Furukawa, is critical: "It indicates different strategies to develop therapeutic compounds ones that bind to a certain type of NMDA receptors very specifically. Being able to target specific subtypes of the receptor is of enormous interest and has great therapeutic potential in a range of illnesses and injuries affecting the brain."


'/>"/>

Contact: Peter Tarr
tarr@cshl.edu
516-367-8455
Cold Spring Harbor Laboratory
Source:Eurekalert  

Related medicine news :

1. Unprecedented accuracy in locating brain electrical activity with new device
2. UT MD Anderson Cancer Center launches unprecedented Moon Shots Program
3. Ibrutinib has unprecedented impact on mantle cell lymphoma
4. Premium Astrology Client Care Team Offers Unprecedented 24-Hour Turnaround Time During March 2013 Reader's Appreciation Month
5. Unprecedented Plastic Surgery SEO Guarantee Announced by JD Media Surge, LLC
6. bioMérieux Partners with Ultimate Labs to Bring Unprecedented Speed to Pathogen Identification for Food, Drug, and Cosmetic Manufacturers
7. Gang members found to suffer unprecedented levels of psychiatric illness
8. Pacific Prime Clients with Aetna Receive Unprecedented Discounts on First Year Insurance Premiums
9. New Hawaiian Jellys “Slip…aaahs” Sandals Provide Unprecedented Comfort and Fashion for Flip Flop Enthusiasts
10. CARRE Foundation selects TGen for unprecedented research into causes of multiple system atrophy
11. An Unprecedented Initiative to Hit Cancer Head On
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Unprecedented structural insights: NMDA receptors can be blocked to limit neurotoxicity
(Date:4/28/2017)... , ... April 28, 2017 , ... ... been previously exposed to more adverse experiences than children in the general population. ... such as abuse, neglect or other family challenges. While no fault of their ...
(Date:4/28/2017)... ... April 28, 2017 , ... Early detection and ... drug safety and minimize the cost of development. In this webinar, sponsored by ... cell lines and for cardiac toxicity using induced pluripotent stem cells (iPSCs). , ...
(Date:4/28/2017)... ... ... Hawkins, Pastor and Overseer at The House of Yahweh in Abilene, Texas, has published a ... does not. Yisrayl says with so many titles and names for the Creator, it’s ... with a little Scripture, backed with a lot of research, the truth is undeniable. ...
(Date:4/28/2017)... ... April 28, 2017 , ... Intellitec Solutions announced the ... implement a Microsoft Dynamics GP solution that integrates to their PointClickCare EHR software ... in long-term care, Brooke Grove now has the capability to achieve its goal ...
(Date:4/28/2017)... ... ... Rob Lowe is a popular actor that has been in many different ... purpose as the host of the “Informed” series. The program focuses on many important ... series focuses on thyroid cancer. , Although thyroid cancer is an uncommon type of ...
Breaking Medicine News(10 mins):
(Date:4/19/2017)... , April 19, 2017 Cardiology devices segment ... projected period The Cardiology Devices segment is likely ... US$ 15 Mn in 2018 over 2017. By the end ... market valuation close to US$ 700 Mn, expanding at a ... segment dominated the Asia Pacific reprocessed ...
(Date:4/19/2017)... DALLAS , April 19, 2017  Vanderbilt University ... first patients in Nashville , Tennesse ... Lower Esophageal Sphincter Stimulation for GERD (LESS GERD) trial. ... to provide long-term reflux control by restoring normal function ... nearly 65 million people in the United ...
(Date:4/19/2017)... HANOVER, N.J. , April 19, 2017 /PRNewswire/ ... conducted by the National Heart, Lung, and Blood ... (NIH) demonstrating that 58% of patients with treatment-naïve ... six months when treated with eltrombopag at the ... 1 . The study evaluated three sequential treatment ...
Breaking Medicine Technology: