β11-12 linker isomerization governs Acid-sensing ion channel desensitization and recovery
- University of Rochester Medical Center, United States
- University of Rochester, United States
- University of Ottawa, Canada
Abstract
Acid-sensing ion channels (ASICs) are neuronal sodium-selective channels activated by reductions in extracellular pH. Structures of the three presumptive functional states, high-pH resting, low-pH desensitized, and toxin-stabilized open, have all been solved for chicken ASIC1. These structures, along with prior functional data, suggest that the isomerization or flipping of the β11-12 linker in the extracellular, ligand-binding domain is an integral component of the desensitization process. To test this, we combined fast perfusion electrophysiology, molecular dynamics simulations and state-dependent non-canonical amino acid cross-linking. We find that both desensitization and recovery can be accelerated by orders of magnitude by mutating resides in this linker or the surrounding region. Furthermore, desensitization can be suppressed by trapping the linker in the resting state, indicating that isomerization of the β11-12 linker is not merely a consequence of, but a necessity for the desensitization process in ASICs.
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Author details
Funding
National Institute of Neurological Disorders and Stroke (R00NS094761)
- David M Maclean
Brain and Behavior Research Foundation (NARSAD Young Investigator Award)
- David M Maclean
Natural Sciences and Engineering Research Council of Canada (RGPIN 2019-06864)
- Maria Musgaard
Canada Research Chairs (950-232154)
- Maria Musgaard
Cystic Fibrosis Foundation (LUECK18G0)
- John D Lueck
National Institute of General Medical Sciences (T32GM068411-15)
- Matthew L Rook
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Cynthia M Czajkowski, University of Wisconsin, Madison, United States
Publication history
- Received: August 15, 2019
- Accepted: February 6, 2020
- Accepted Manuscript published: February 7, 2020 (version 1)
- Version of Record published: February 25, 2020 (version 2)
Copyright
© 2020, Rook et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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- Cell Biology
- Neuroscience
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- Neuroscience
