Cryo-EM Reveals First 3D Map of ASIC1a Channel, Opening New Avenues for Stroke Drug Development
核心洞察
Scientists at Oregon Health & Science University have mapped six major conformations of the acid-sensing ion channel ASIC1a (搜索) in three-dimensional detail for the first time.
The study, published in Nature Structural & Molecular Biology, used cryo-electron microscopy to capture structural states by varying extracellular pH exposure.
Blocking ASIC1a (搜索) has been shown to be neuroprotective, and the new structural blueprint could guide design of selective inhibitors to protect brain tissue during stroke (搜索).
Researchers at Oregon Health & Science University (OHSU) have produced the first high-resolution, three-dimensional map of six major conformations of ASIC1a (搜索), an acid-sensing ion channel in the brain implicated in learning, memory, fear-related behavior, and neuronal damage following stroke (搜索). The findings, published today in Nature Structural & Molecular Biology, provide a structural blueprint that could accelerate the rational design of drugs aimed at protecting brain tissue during ischemic events.
"Previous studies show that when you block this channel, it can be neuroprotective," said senior author Isabelle Baconguis, Ph.D., assistant professor in the OHSU Vollum Institute. "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 (搜索)."
Capturing Conformational States with Cryo-EM
The team leveraged state-of-the-art cryo-electron microscopy (cryo-EM) housed at OHSU's South Waterfront Campus to visualize ASIC1a (搜索) at unprecedented resolution. Using recombinant DNA technology, the researchers expressed the human gene to generate human proteins for imaging. Because acid-sensing ion channels respond to variations in extracellular pH within the central and peripheral nervous systems, the scientists were able to capture six distinct conformations by systematically varying the channels' exposure to acidity.
"In our bodies, there are locations where cells undergo different pH conditions, especially in the brain," Baconguis explained. "In neuronal injuries such as stroke (搜索), where brain tissue undergoes a drop in pH, these channels can be activated causing tissue damage."
Translational Potential in Stroke (搜索)
The structural data arrive at a time of growing interest in ASIC1a (搜索) as a therapeutic target. Scientists in Australia are already investigating a molecule derived from spider venom that explicitly targets ASIC1a to improve outcomes in heart attacks and stroke (搜索). The new images from OHSU provide a detailed molecular blueprint that could enable the design of more selective small-molecule inhibitors capable of blocking this specific channel without off-target effects.
"The sooner you can protect brain tissue from damage, the less severe disability stroke (搜索) survivors will have," Baconguis said. "Time is of the essence when it comes to stroke."
Study Details and Funding
The international collaboration included co-authors James Cahill, Kimberly A. Hartfield, Ph.D., and Craig Yoshioka, Ph.D., of OHSU; Stephan Alexander Pless, Ph.D., Nadine Ritter, Ph.D., and Mette Homann Poulsen, Ph.D., of the University of Copenhagen; and Stephanie Andrea Heusser, Ph.D., of the University of Copenhagen and Linköping University in Sweden.
The research was supported by the National Institutes of Health through grant awards R24GM154185 and RO1GM138862 from the National Institute of General Medical Sciences (NIGMS), as well as the Lundbeck Foundation under grant award R313-2019-571. Electron microscopy was performed at the Multiscale Microscopy Core, part of OHSU's university-shared resource cores.