CSHL’s Hiro Furukawa describes important structure of brain protein

By Daniel Dunaief

Following a relentless drive to succeed, scientists have a great deal in common with athletes.

In addition to putting in long hours and dedicating considerable energy to improving their results, these talented professionals also enjoy moments of success — large and small — as opportunities to appreciate the victories and then build to greater challenges.

And so it is for Hiro Furukawa, a Professor at Cold Spring Harbor Laboratory.

Working with a team of scientists including at Emory University, Furukawa recently published a paper in the prestigious journal Nature in which he demonstrated the long-sought structural process that leads to the opening of an important channel in the brain, called the NMDAR receptor.

When this cellular channel doesn’t function correctly, it can lead to numerous diseases, including Alzheimer’s and depression. Understanding the structural details of this channel could, at some point in future research, lead to breakthrough treatments.

“Each moment of discovery is exciting and priceless,” Furukawa explained. “When I finally see what I have sought for many years — in this case, the mechanism of NMDAR channel opening — it fills me with immense euphoria, followed by a sense of satisfaction.”

That sounds like the kind of mountaintop moment that star athletes whose achievements people applaud share once they’ve reached a long-desire milestone, like, perhaps, winning a gold medal in the Olympics.

The thirst for more for Furukawa, as it is for those with a passion for success in other fields beyond science and athletics, is unquenchable and unrelenting.

“This feeling is fleeting,” he added. “Within a few hours, a flurry of new questions arising from the discovery begins to occupy my mind.”

Indeed, Furukawa suggested that he expects that many other scientists share this experience.

Forming a winning team

Furukawa and Stephen Traynelis, Professor and Director in the Department of Pharmacology and Chemical Biology at Emory University School of Medicine in Atlanta, started to work together on a series of modulators for the NMDAR protein about eight years ago.

This particular protein binds to the neurotransmitter glutamate and to glycine, which is another compound. Once bound to both, the channel, as if responding to the correct combination in a garage door, opens, creating electrical signals that contribute to brain functions.

To study the way the binding of these molecules opened the channel, the researchers needed to figure out how to keep the receptor in the open position.

That’s where a combination of work in the labs of Traynelis and Dennis Liotta, also a Professor at Emory, came in. Liotta’s lab made over 400 analogs that Traynelis ran in his lab.

Liotta created a compound called EU-1622-A, which is now known as EU-1622-240, that upregulates NMDAR activity, Furukawa explained.

“We used cryo-EM [electron microscopy] to capture the NMDAR structure with the compound, validated its conformation through electrophysiology and elucidated the activation mechanism,” he said.

Incorporating EU-1622-240 along with glycine and glutamate into the GluN1-2B NMDAR sample, which is a specific subtype and is the easiest to work with, enabled a visualization of the open channel.

Furukawa described the compound Traynelis created at Emory as the “key factor in capturing the open channel conformation.”

Determining the structure of a functioning protein can provide clues about how to alter those that may be contributing to the onset or progression of a disease.

To be sure, Furukawa recognizes the work as one step in what’s likely to involve an extensive research journey.

“We still have a long way to go, but we’ve made progress,” Furukawa said. “In this study, a compound bound to NMDAR gave us a clue on how to control the frequency of ion channel openings. Both hyperactive and hypoactive functions of NMDAR ion channels have been implicated in Alzheimer’s disease, so being able to regulate NMDAR activity would be significant.”

Furukawa can’t say for sure if this compound could alleviate the symptoms of certain diseases, but it serves as a new series of potentially clinically relevant options to test.

The researchers are developing a method to purify NMDAR proteins from animal tissues. Once they accomplish that task, they should be able to isolate NMDAR from Alzheimer’s brains to compare them to a normally functioning protein.

Furukawa suggested that it’s probable that specific NMDAR conformations are stabilized to different extents in various diseases compared to normal brains.

The researchers have not yet presented this work at meetings. First author Tsung-Han Chou, who is a postdoctoral fellow in Furukawa’s lab, plans to present the work at upcoming conferences, such as the Biophysical Society Meeting.

The review process for the research proceeded quickly, as the team submitted the paper in February of this year. 

Next steps

As for what’s next, Furukawa suggested that the team planned to solidify their findings.

“We must determine if the channel opening mechanism applies to other types of NMDARs,” he said. “Although we observed that EU1622-A compound binds to NMDAR, its structure was not sufficient resolved.”

To facilitate the re-design of EU1622-240, the scientists will need to improve the cryo-EM map resolution.

Traynelis, meanwhile, said that he and Liotta are synthesizing new modulators in this class and related classes and are working on mechanisms of action for this series at all NMDA receptors as well as actions in neuronal systems.

“We have a robust synthetic program with our collaborator [Liotta], whose laboratory is synthesizing many new modulators in this class and related classes,” Traynelis explained.

Traynelis added that his goal is to “develop new medicines to address unmet clinical needs. We want to find new and effective therapeutic treatments that help patients.”

The Emory professor is excited about the “potential development of positive NMDA receptor allosteric modulators that could enhance NMDA receptor function.”

Broader perspective

Furukawa, who lives in Cold Spring Harbor and whose sons Ryoma, 16 and Rin, 13, attend senior and junior high school, respectively, was interested in international politics and economics when he attended Tufts University as an undergraduate.

These non-science topics provide additional perspective that enrich his life.

“I remain very interested in understanding history and the reasons behind current events in Europe, the Middle East, and the U.S.,” he said. “This endeavor is far more challenging than decoding NMDAR structures and functions.”

As for his collaborations, Furukawa suggested that the findings from this research inspire him to continue to search for more answers and greater scientific achievements.

“We will continue to unravel these mysteries in future studies,” Furukawa said. “The best is yet to come.”