Scientists have revealed the structure of a critical receptor in the brain associated with learning, memory, behavior and mood.
The new research, published in the journal Science, is the first to reveal the structure of AMPA receptors in their natural state. This discovery could lead to new insight about the mechanism behind a wide range of nervous system disorders and diseases.
"These are the fundamental electrical switches of the brain," said the senior author. "If these switches don't work right, then the brain doesn't function. It can lead to seizures, memory loss, and neurodegenerative conditions like Alzheimer's disease."
Researchers used cryo-electron microscopy and targeted mass spectrometry to reveal the architecture and subunit arrangement of AMPA receptors in rodents. AMPA receptors are activated by the neurotransmitter glutamate, forming permeable ion channels that carry signals between cells throughout the nervous system.
Authors find that receptor subunits are arranged non stochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. Cryo-EM maps define the structure for S2-M4 linkers between the ligand binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating.
By discerning the makeup of the working structure in rodents, scientists can isolate the same structures in post-mortem samples of human brains and make comparisons. They may then be able to determine differences between the structure and organization of healthy AMPA receptors and those in people with neurodegenerative diseases.
"It's super exciting," the senior author said. "There is no guarantee, but what we want to do is understand how these receptors are different in devastating human diseases for which there are presently few, if any, treatments. If we can get new insights about the mechanism of the disease, it could provide novel approaches for therapies."
The new discovery comes by way of a technique that's revolutionizing the field of structural biology.
Native structure of AMPA receptor elucidated!
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