ASIC1a Protein Mapping for Novel Stroke Treatments

A three-dimensional visualization of ASIC1a, a membrane protein linked to brain function and stroke, displayed on a computer in the lab of Isabelle Baconguis, Ph.D., at OHSU. New research revealed six major conformations of the protein, providing a potential blueprint for future drug development.
Photo Credit: OHSU/Christine Torres Hicks

Scientific Frontline: Extended "At a Glance" Summary: Mapping the ASIC1a Membrane Protein

The Core Concept: Researchers have successfully mapped six major conformations of human acid-sensing ion channel 1a (ASIC1a), a critical brain membrane protein associated with learning, memory, fear-related behavior, and stroke-induced tissue damage.

Key Distinction/Mechanism: Acid-sensing ion channels respond directly to variations in extracellular pH. During neuronal injuries such as strokes, the localized drop in brain tissue pH activates the ASIC1a channels, which subsequently triggers cellular damage.

Major Frameworks/Components:

• Cryo-Electron Microscopy (Cryo-EM): The advanced structural imaging technology used to capture the protein's intricate, three-dimensional states.
• Recombinant DNA Technology: Utilized to express the specific human gene and generate the human proteins required for high-resolution imaging.
• Conformational Plasticity: The six distinct structural states of the protein, which were captured by systematically altering environmental acidity.

Branch of Science: Structural Biology, Molecular Neuroscience, and Pharmacology.

Future Application: The detailed structural blueprint provides a foundation for developing novel pharmacological inhibitors. These targeted drugs could block the ASIC1a channel during a stroke, delaying tissue death and improving patient outcomes. Related research in Australia is already exploring spider venom derivatives to target this exact channel.

Why It Matters: Time is critical during a stroke. Inhibiting the activation of ASIC1a serves as a powerful neuroprotective strategy, preserving vulnerable brain tissue from irreversible damage and reducing severe disability in stroke survivors.

This cryo-EM structure of acid-sensing ion channel 1a, known as ASIC1a, reveals a previously unidentified conformational state. The gray lines represent the boundaries of the cell's membrane, showing how the protein sits within it, with the "out" label indicating the side facing the outside of the cell (extracellular) and "in" representing the inside (intracellular).
Image Credit: OHSU/Baconguis lab

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

Researchers used a state-of-the-art cryo-electron microscope housed at 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 strokes, said senior author Isabelle Baconguis, PhD, an assistant professor at 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."

Isabelle Baconguis, Ph.D.
Photo Credit: OHSU

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

OHSU researchers used recombinant DNA technology to express the human gene to generate human proteins, which they imaged using cryo-EM. Because acid-sensing ion channels respond to variations in 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 the disability stroke survivors will have," Baconguis said. "Time is of the essence when it comes to stroke."

Funding: The research was supported by the National Institutes of Health, grant awards R24GM154185 and R01GM138862 from the National Institute of General Medical Sciences (NIGMS), and the Lundbeck Foundation, grant award R313-2019-571. Electron microscopy was performed at the Multiscale Microscopy Core, part of OHSU's university shared resource cores. 

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Published in journal: Nature Structural & Molecular Biology

Title: Conformational plasticity of human acid-sensing ion channel 1a

Authors: James Cahill, Kimberly A. Hartfield, Stephanie Andrea Heusser, Nadine Ritter, Mette Homann Poulsen, Craig Yoshioka, Stephan Alexander Pless, and Isabelle Baconguis

Source/Credit: Oregon Health & Science University | Erik Robinson

Edited by: Scientific Frontline

Reference Number: bio071626_01

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