Navigation Links
Unprecedented detail of intact neuronal receptor offers blueprint for drug developers
Date:8/26/2014

Argonne, Ill. Scientists succeeded in obtaining an unprecedented view of a type of brain-cell receptor that is implicated in a range of neurological illnesses, including Alzheimer's disease, Parkinson's disease, depression, schizophrenia, autism, and ischemic injuries associated with stroke.

The team of biologists at Cold Spring Harbor Laboratory used the U.S. Department of Energy's Advanced Photon Source at Argonne National Laboratory to get an atomic-level picture of the intact NMDA (N-methyl, D-aspartate) receptor should serve as template and guide for the design of therapeutic compounds.

The NMDA receptor is a massive multi- subunit complex that integrates both chemical and electrical signals in the brain to allow neurons to communicate with one another. These conversations form the basis of memory, learning, and thought, and critically mediate brain development. The receptor's function is tightly regulated: both increased and decreased NMDA activities are associated with neurological diseases.

Despite the importance of NMDA receptor function, scientists have struggled to understand how it is controlled. In work published recently in Science, CSHL Associate Professor Hiro Furukawa and Erkan Karakas, Ph.D., a postdoctoral investigator, use a type of molecular photography known as X-ray crystallography to determine the structure of the intact receptor. Their work identifies numerous interactions between the four subunits of the receptor and offers new insight into how the complex is regulated. The X-ray work was done with the National Institute for General Medical Sciences and National Cancer Institute Collaborative Access Team (GM/CA) beamline at the APS and a beamline at SPring 8.

"Previously, our group and others have crystallized individual subunits of the receptor just fragments but that simply was not enough," says Furukawa. "To understand how this complex functions you need to see it all together, fully assembled."

For such a large complex, this was a challenging task. Using an exhaustive array of protein purification methods, Furukawa and Karakas were able to isolate the intact receptor. Their crystal structure reveals that the receptor looks much like a hot air balloon. "The 'basket' is what we call the transmembrane domain. It forms an ion channel that allows electrical signals to propagate through the neuron," explains Furukawa.

An ion channel is like a gate in the neuronal membrane. Ions, small electrically charged atoms, are unable to pass through the cell membrane. When the ion channel "gate" is closed, ions congregate outside the cell, creating an electrical potential across the cell membrane.

When the ion channel "gate" opens, ions flow in and out of the cell through the channel pores. This generates an electrical current that sums up to create pulses that rapidly propagate through the neuron. But the current can't jump from one neuron to the next. Rather, the electrical pulse triggers the release of chemical messengers, called neurotransmitters. These molecules traverse the distance between the neurons and bind to receptors, such as the NMDA receptor, on the surface of neighboring cells. There, they act much like a key, unlocking ion channels within the receptor and propelling the electrical signal across another neuron and, ultimately, across the brain.

The "balloon" portion of the receptor that Furukawa describes is found outside the cell. This is the region that binds to neurotransmitters. The structure of the assembled multi-subunit receptor complex, including the elusive ion channel, helps to explain some of the existing data about how NMDA receptors function. "We are able to see how one domain on the exterior side of the receptor directly regulates the ion channel within the membrane," says Furukawa. "Our structure shows why this particular domain, called the amino terminal domain, is important for the activity of the NMDA receptor, but not for other related receptors."

This information will be critical as scientists work to develop drugs that control the NMDA receptor. "Our structure defines the interfaces where multiple subunits and domains contact one another," says Furukawa. "In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases."


'/>"/>

Contact: Tona Kunz
tkunz@anl.gov
630-252-5560
DOE/Argonne National Laboratory
Source:Eurekalert

Related biology news :

1. Research gives unprecedented 3-D view of important brain receptor
2. Technofossils -- an unprecedented legacy left behind by humans
3. Study of complete RNA collection of fruit fly uncovers unprecedented complexity
4. Arctic warmth unprecedented in 44,000 years, reveals ancient moss
5. New microscopes at NIH reveal live, developing cells in unprecedented 3-D clarity
6. An unprecedented threat to Perus cloud forests
7. Unprecedented control of genome editing in flies promises insight into human development, disease
8. Genome sequencing provides unprecedented insight into causes of pneumococcal disease
9. Study by Haverford College professor reveals unprecedented impact of Deepwater Horizon on deep ocean
10. Oregon study details brain pathways linking visual function, running
11. Scientists launch far-ranging campaign to detail Front Range air pollution
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/30/2017)... LOS ANGELES , March 30, 2017  On ... Hack the Genome hackathon at ... This exciting two-day competition will focus on developing health ... experience. Hack the Genome is ... has been tremendous. The world,s largest companies in the ...
(Date:3/30/2017)... , March 30, 2017 Trends, opportunities ... (physiological and behavioral), by technology (fingerprint, AFIS, iris recognition, ... recognition, and others), by end use industry (government and ... immigration, financial and banking, and others), and by region ... , Asia Pacific , and ...
(Date:3/28/2017)... PUNE, India , March 28, 2017 ... (Analog, IP, Biometrics), Hardware (Camera, Monitors, Servers, Storage Devices), ... Maintenance), Vertical, and Region - Global Forecast to 2022", ... 30.37 Billion in 2016 and is projected to reach ... 15.4% between 2017 and 2022. The base year considered ...
Breaking Biology News(10 mins):
(Date:10/10/2017)... Oct. 10, 2017 SomaGenics announced the receipt ... to develop RealSeq®-SC (Single Cell), expected to be the ... RNAs (including microRNAs) from single cells using NGS methods. ... need to accelerate development of approaches to analyze the ... "New techniques for measuring levels of mRNAs in ...
(Date:10/10/2017)... ... October 10, 2017 , ... ... 13 prestigious awards honoring scientists who have made outstanding contributions ... scheduled symposium during Pittcon 2018, the world’s leading conference and exposition for laboratory ...
(Date:10/9/2017)... ... October 09, 2017 , ... The award-winning American Farmer television series ... 2018. American Farmer airs Tuesdays at 8:30aET on RFD-TV. , With global population ... challenge of how to continue to feed a growing nation. At the same time, ...
(Date:10/9/2017)... , ... October 09, 2017 , ... ... four-tiered line of medical marijuana products targeting the needs of consumers who are ... of Kindred takes place in Phoenix, Arizona. , As operators of two successful ...
Breaking Biology Technology: