Glutamate signalling in the brain: first three-dimensional images capture AMPA in action

Written by Hannah Makin, Future Science Group

Recent findings published in Nature have captured the first three-dimensional images of the AMPA-subtype glutamate receptor when it is activated by glutamate.
These findings provide researchers with a greater understanding of the receptor in action, which may help towards the development of therapeutics for neurological disorders associated with defects in glutamate signalling.

In previous studies, the structure of the AMPA alone was identified. As well as this, the receptor’s structure when in complex with other proteins (which regulate the strength and speed of synaptic connections) has also been deciphered.

However, in this new study, researchers at the Columbia University Medical Center (NY, USA) aimed to investigate the structure of the AMPA receptor specifically when activated by glutamate.

Cryo-electron microscopy allowed researchers to investigate the AMPA receptor in apo – antagonist and agonist-bound states.

By combining the two-dimensional images that were captured with this technique, researchers were then able to form three-dimensional structural images of the AMPA receptor whilst in action.

Senior author of this study and Professor at the University of Columbia, Alexander Sobolevsky, explained the significance of these findings: “With our new findings, we can now, for the first time, visualize how the neurotransmitter glutamate opens glutamate receptor ion channels. This is the fundamental process that directly affects learning and memory, and finding its structural determinants has been the primary goal of molecular neuroscience since the ’90s.”

With the findings of this recent study, scientists now have a greater insight into the role of AMPA during excitatory neurotransmission, and also into the gating mechanisms of the family of ionotropic glutamate receptors more broadly.

First author of this study, Edward Twomey (Columbia University), stated: “These new fundamental discoveries have implications for our understanding of neurotransmission by glutamate, our brain’s major neurotransmitter. Understanding these processes will impact future studies on glutamate receptor signalling in neurodegenerative diseases as well as drug design.”

Sources:Twomey EC, Yelshanskaya MV, Grassucci RA, Frank J, Sobolevsky AI. Channel opening and gating mechanism in AMPA-subtype glutamate receptors. Nature. doi:10.1038/nature23479 (2017)