Glutamate receptors are the most prevalent molecular “switches” mediating communication between nerve cells in the brain. They play keys roles in nearly all human behaviors, from learning to memory and movement, as simply a few examples. Glutamate receptors are also the targets of a broad range of therapeutic agents, from anti-seizure medications to antidepressants.
Glutamate receptors do not function alone, however: they form complexes with other proteins called transmembrane AMPA-receptor regulatory proteins, or TARPs. These accessory proteins modulate the properties of the receptor and are made in different regions of the brain, thus giving rise to brain-region-specific receptor function. How glutamate receptors interact with TARPs has been a long-standing question.
In a Nature paper, published online on July 1, 2016, OHSU researchers from the Vollum Institute and the Department of Biomedical Engineering in the School of Medicine, describe the long sought after structure of a glutamate receptor – TARP complex, thus showing how the proteins interact with each other. The team led by Eric Gouaux, Ph.D., Yan Zhao, Ph.D., and Shanshuang Chen, Ph.D., used x-ray crystallography and single particle cryo-electron microscopy (cryo-EM) to capture images of the TARP structure. Their findings offer clues into how TARPs modulate receptor function and provide a template for receptor – TARP specific design of novel small molecules, entities that might prove useful as therapeutic agents.
Drs. Zhao and Chen, both postdoctoral researchers in the Gouaux Lab, contributed equally to the research reported in “Architecture of fully occupied GluA2 AMPA receptor–TARP complex elucidated by cryo-EM.” In addition to Eric Gouaux, Craig Yoshioka, Ph.D., from the Department of Biomedical Engineering and Isabelle Baconguis, Ph.D. from the Vollum Institute, contributed to this paper.
Shanshuang Chen is supported by an American Heart Association postdoctoral fellowship (16POST27790099).This work was supported by the NIH (Eric Gouaux, NS038631). Eric Gouaux is an investigator with the Howard Hughes Medical Institute.