This receptor is present on almost every neuron in the human brain and is involved in learning and memory. NMDA receptors also have been implicated in several neurological and psychiatric conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia and depression.
But drug companies have had little success developing clinically effective drugs that target this receptor.
Now, researchers at Oregon Health & Science University's Vollum Institute believe they may understand why. And what they've discovered may help in the development of new therapies for these conditions.
In a paper published in the current issue of the Journal of Neuroscience, OHSU scientists describe their work on NMDA receptors. There are various types of NMDA receptors, resulting from differences in the protein components that make up the receptor. These differences in the protein components produce receptors with varying properties.
As drug companies have worked to develop compounds that manipulate the activity of these receptors, the focus of much of this drug discovery effort has been on a specific NMDA receptor subtype. In their Journal of Neuroscience paper, the OHSU scientists describe their discovery — that the specific receptor subtype that drug companies have seen as a target is an almost nonexistent contributor of NMDA receptor action.
What does exist, the OHSU scientists found, was a different kind of NMDA receptor subtype — one containing two specific protein components, called GluN2A and GluN2B. NMDA receptors containing these two components were not thought to be very common. The OHSU study found that not only was this NMDA receptor subtype more common than previously believed, it was the most common subtype at synapses. And it was far more common than the receptor subtype that has been the target of drug development efforts.
"What our paper shows is that one reason no drugs have worked well to this point may be because that particular NMDA receptor subtype isn't there in high quantities. The target they've been looking for isn't the target that's there," said Ken Tovar, Ph.D., a senior postdoctoral fellow at the Vollum Institute. Tovar's co-authors on the paper were Gary Westbrook, M.D., senior scientist and co-director of the Vollum Institute, and Matthew McGinley, Ph.D., a former graduate student in the Westbrook laboratory.
Tovar said these findings could provide a new target for drug development.
"If you know what's there, then you know what to go after — you just have to figure out how to do it," Tovar said.
The OHSU study also provides clues into how the function of this most common NMDA receptor subtype might be manipulated. Highly specific drugs interact with either GluN2A or GluN2B. Tovar and colleagues demonstrated that when GluN2A and GluN2B coexist in the same receptor, molecules that targeted GluN2A change the behavior of the receptor in ways that could be clinically beneficial.
"NMDA receptors have been implicated in a diverse list of neurological and psychiatric conditions. Thus, the more we know about how to modulate the behavior of the receptors that are there — at synapses — the greater chance we have of finding drugs to treat these conditions," Tovar said.
"From the perspective of drug development, knowing the nature of your target is one way to keep drug development costs down," said Tovar. "Spending resources investigating a target that turns out to be unimportant means those costs get passed on to the drugs that are effective."
The study was funded by the National Institutes of Health, grants NS 26494 and MH 46613.About the OHSU Vollum Institute
Todd Murphy | EurekAlert!
Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University
The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy