Opening the gates of an elegant brain receptor

The glutamate receptor is an important player in nerve signaling and exceptionally high-resolution images of protein interactions are revealing how these receptors operate, which could have an impact on future targets for a wide variety of neurodegenerative diseases, announced the National Institutes of Health (NIH) on Monday.

Glutamate receptor imaging that details the role they play in the flow of ions in cell membranes has eluded scientists until a research team, including Sriram Subramaniam, PhD, from the National Cancer Institute (NCI) and Mark Mayer, PhD, from the NIH, devised a technique compiling "tens of thousands of molecular images" using cryo-electron microscopy. These subcellular images have a resolution at an order of about seven angstrom.

"Not in a million years would I have dreamed that a cell receptor would work this way to open and close the gate for ion flow," Subramaniam said in an NIH statement. "It is really satisfying to be able to decipher the inner workings of such an elegant molecular machine."

Dysfunction in these receptors has been implicated in a range of diseases, from Alzheimer's, Parkinson's and depression to some types of cancer. The knowledge that researchers have gleaned about these and other subcellular structures have been published in both Nature and in the Proceedings of the National Academy of Sciences.

Subramaniam et al elucidated some of these innerworkings of these receptors in varying stages, active and desensitized, on August 3 in Nature: "We show that transition to the active state involves a ‘corkscrew’ motion of the receptor assembly, driven by closure of the ligand-binding domain."

"We are now poised to analyze structures of a wide variety of biologically and medically relevant multi-protein complexes and membrane protein assemblies, which have historically represented the most challenging frontier in structural biology," said Subramaniam in the NIH statement.