Newly published research by a former NARSAD Young Investigator Grantee provides an unprecedented view of a key brain receptor whose malfunction is implicated in depression, schizophrenia, Alzheimer’s and Parkinson’s diseases.

The receptor―one of many kinds of portals that sit on the surface of cells and enable them to interact with their surroundings―is called an NMDA (N-methyl, D-aspartate) receptor. It is found in abundance throughout the brain, on neurons that handle “excitatory” signals that facilitate nerve transmissions from cell to cell. Understanding how the NMDA receptor function is compromised in many disorders and diseases has been a longstanding and unsolved challenge for neuroscientists.

Erkan Karakas, Ph.D. (recipient of a 2009 NARSAD Young Investigator Grant) has worked with Associate Professor Hiro Furukawa, Ph.D., at Cold Spring Harbor Laboratory for several years to more fully flesh out how the NMDA receptor functions. Not until now, however, has the team succeeded in assembling a view of the receptor in its “full-length” form.

“To understand how the whole complex functions, you have to see it all together, fully assembled,” Drs. Karakas and Furukawa explain. After painstaking years of work, they finally solved the complete puzzle, and their results were published in Science on May 30th. Most important, this work reveals how the extracellular portion of NMDA receptors directly controls what is called the “ion channel.” Ion channels allow charged atoms to flow through the outside and inside of cells. This new insight about the NMDA receptor explains how it responds to excitatory signals from the neurotransmitter glutamate.

The researchers report that the new work fills in missing gaps of information, helping explain how NMDA receptors are distinct from what are called AMPA receptors, other common neuronal receptors that handle excitatory signals.

This new fully assembled view will enable further experiments to examine the function and dysfunction of NMDA receptors with new precision. The findings should also serve as an important blueprint for the development of novel treatments that can control NMDA receptors without affecting receptors in other kinds of cells, thus minimizing side effects.  

Read the paper abstract.