Scientists have for the first time revealed the structure surrounding important receptors in the cerebral hippocampus, the site of memory and learning.
The study, performed at Oregon Health & Science University, published today in the journal Nature.
The new study focuses on the organization and function of receptors for glutamate, a type of neurotransmitter receptor involved in sensing signals between nerve cells in the hippocampus region of the brain. The study reveals the molecular structure of three major glutamate receptor complexes in the hippocampus.
The results can be immediately useful in the development of drugs for conditions such as epilepsy, said lead author Eric Gouaux, Ph.D., a senior researcher at the OHSU Vollum Institute, Jennifer and Bernard Lacroute endowed with a research chair in neuroscience and researcher with the Howard Hughes Medical Institute.
“Epilepsy or seizure disorders can have many causes,” he said. “If you know the underlying cause of a particular person’s seizure activity, then you may be able to develop small molecules to modulate that activity.”
Working with a mouse model, OHSU researchers made the breakthrough by developing a chemical reagent based on monoclonal antibodies to isolate the receptor and the complex of subunits that surround it. They then imaged the assembly using state-of-the-art cryoelectron microscopy at the Pacific Northwest Cryo-EM Center, located on the South Waterfront campus of OHSU in Portland.
Gouaux predicts that the technique will transform structural biology.
“It really opens the door to specifically targeting molecules that need to be targeted in order to treat a particular condition,” he said. “A lot of drug development is based on structure, where you see what the lock looks like and then you develop a key. If you don’t know what the lock looks like, then it’s a lot harder to develop a key. . “
Previously, scientists had to rely on mimicking real receptors by artificially making receptors by combining segments of DNA in tissue culture. However, this technique has obvious shortcomings.
“It doesn’t work perfectly because the real receptors are surrounded by a constellation of additional subunits, sometimes unknown before,” Gouaux said.
New monoclonal antibody reagents, also developed at OHSU, allowed scientists to isolate actual glutamate receptors from brain tissue in mice. They were then able to image these samples in near atomic detail using cryo-EM, which allowed them to capture the entire assembly of three types of glutamate receptors with their helper subunits.
“Previously, it was impossible to do this because we had no good way to isolate the molecules and no way to see what they looked like,” Gouaux said. “So this is a super exciting development.”
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Material provided by Oregon University of Health and Sciences. Original written by Erik Robinson. Note: Content can be changed for style and length.