Three Dimensional Structure Revealed of an Important Neuronal Receptor

NMDA receptor

 

Three Dimensional Structure Revealed of an Important Neuronal Receptor

 

Two new studies, from two different research institutions have reported very similar findings less than a month apart.  Both groups of researchers are very excited about the results of their research and its potential to lead to new therapeutic treatments for neurodegenerative diseases such as PARKINSON’S DISEASE, Huntington’s Disease and Alzheimer’s Disease as well as depression and schizophrenia.  Their excitement comes from their newly visualized structure of the NMDA receptor giving insights into its complex function that plays such a vital role in neurological processes in the brain.

 

The first group of investigators published their data in the journal Science on May 29, 2014. Dr. Hiro Furukawa, an associate professor of biology, and his graduate student, Dr. Erkan Karakas, lead the team of researchers from Cold Spring Harbor Laboratory, a private, non-profit research institution in Cold Spring Harbor, New York. According to Dr. Furukawa, “Previously, our group and others have crystallized individual subunits of the receptor – just fragments – but that simply was not enough.  To understand how this complex functions you need to see it all together, fully assembled.”

 

The second group of researchers are part of the Vollum Institute at Oregon Health and Science University in Portland, Oregon.  They published their data on June 27th in the journal Nature. Dr. Eric Gouaux led a team of six investigators.  He is a senior scientist and also an investigator with the Howard Hughes Medical Institute.  An excited Dr. Gouaux said: “The NMDA receptor is one of the most essential, and still sometimes mysterious, receptors in our brain.  Now, with this work, we can see it in fascinating detail.”

 

Both groups worked with the same innovative molecular photography called x-ray crystallography.  X-ray crystallography is not a new imaging technique but a way to examine the structure of a molecule using x-rays deflected from the surface of a collection of those molecules that form a crystal structure.  In this case, the researchers were examining the NMDA receptor, one of the most important for facilitating communication between neurons. This receptor is important in facilitating learning and memory.  Malfunctions in this receptor are responsible for a wide range of neurological diseases, including PARKINSON’S DISEASE.

 

This receptor is called NMDA, which stands for N-methyl, d-aspartate.  Its functional importance has been long understood, however its molecular structure and how it is controlled has been eluding researchers.  The receptor is a complex composition of subunits, whose individual actions have been extensively documented in over three decades of research.  Each unit has unique properties and operates in a distinct manner.  Disturbances in these subunits causing either over or under activity are responsible for various neurological disorders.  Until now understanding the interactions between the subunits and their total integration into the complex receptor has been limited.

 

Revealing the three dimensional structure of this receptor molecule has been an exhausting, tedious and time consuming labor. The image of the receptor that emerged  from this research has been compared to a bouquet of flowers, a mushroom or a hot air balloon.  It is this “balloon” part of the receptor that enables the cell to communicate through neurotransmitters, such as dopamine.  Through visualization of the entire structure it is possible to see how the actions of one sub-unit regulates the response of a different sub-unit on the other side of the receptor and how each of the sub-units contribute to the activity of the NMDA receptor.

 

With this knowledge, scientists will be better able to develop specific treatments to control the NMDA receptor and affect their role in neurodegenerative diseases. Dr. Furukawa said,  “Our structure defines the interfaces where multiple subunits and domains contact one another.  In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”

 

E. Karakas, H. Furukawa. Crystal structure of a heterotetrameric NMDA receptor ion channelScience, 2014; 344 (6187): 992 DOI:10.1126/science.1251915

Chia-Hsueh Lee, Wei Lü, Jennifer Carlisle Michel, April Goehring, Juan Du, Xianqiang Song, Eric Gouaux. NMDA receptor structures reveal subunit arrangement and pore architectureNature, 2014; DOI: 10.1038/nature13548

 

Review by Marcia McCall

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