Six Molecular Snapshots Reveal How a Brain Channel Changes Shape

Scientists have for the first time mapped in exquisite, three-dimensional detail six major conformations of a membrane in the brain related to learning, memory and fear-related behavior.

The study, led by researchers at Oregon Health & Science University, published today in Nature Structural & Molecular Biology.

Researchers used state-of-the-art cryo-electron microscopy housed in OHSU’s South Waterfront Campus to capture the most detailed view yet of a specific type of membrane protein: an acid-sensing ion channel known as ASIC1a.

The findings could form the blueprint for drug development useful in treating stroke, said senior author Isabelle Baconguis, Ph.D., assistant professor in the OHSU Vollum Institute.

“Previous studies show that when you block this channel, it can be neuroprotective,” Baconguis said. “If you’re able to design a drug that infuses an inhibitor to this channel, it could lengthen the survival of the tissue in cases of stroke.”

Already, scientists in Australia are using a molecule derived from spider venom that explicitly targets ASIC1a to improve outcomes in heart attacks and stroke.

OHSU researchers used recombinant DNA technology to express the human gene to generate human proteins they imaged using cryo-EM. Because acid-sensing ion channels respond to variations of extracellular pH in the central and peripheral nervous systems, researchers were able to capture six distinct conformations by varying their exposure to acidity.

“In our bodies, there are locations where cells undergo different pH conditions, especially in the brain,” Baconguis said. “In neuronal injuries such as stroke, where brain tissue undergoes a drop in pH, these channels can be activated causing tissue damage.”

The images provide a blueprint for designing new drugs capable of inhibiting this one specific acid-sensing ion channel in cases of stroke.

“The sooner you can protect brain tissue from damage, the less severe disability stroke survivors will have,” Baconguis said. “Time is of the essence when it comes to stroke.”