# Acid-Sensing Ion Channel gating: Conformations and Consequences

> **NIH NIH R35** · UNIVERSITY OF ROCHESTER · 2021 · $385,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Extracellular pH is a highly dynamic and ubiquitous signal and many cell types exhibit robust
electrophysiological responses upon extracellular acidification, particularly in the nervous system. Acid-sensing
ion channels (ASICs) are thought to mediate the majority of these responses since various ASIC subunits are
expressed at high levels in many neuronal types and genetic ablation of ASIC subunits dramatically reduces
acid-evoked responses. Consequently, ASICs are vital players in cell death following ischemic stroke. However,
ASICs are more than simply an `extracellular acid alarm'. Genetic deletion, or pharmacological manipulation, of
specific ASIC subunits can produce a wide array of phenotypes ranging from attenuated fear learning, deficits
in pain and mechanosensation, problems in cardiac autonomic regulation and the baroreflex and impairment of
the epithelial to mesenchymal transition in various cancer cells. These myriad roles of ASICs have motivated
structural and biophysical investigation, leading to crystal or cryo-EM structures of chicken ASIC1 in the resting,
toxin-stabilized open and desensitized states. This structural data, combined with functional experiments, have
led to a general outline of how ASICs function. Briefly, protonation of key acidic residues in the extracellular
domain, in regions known as the palm domain and the acidic pocket, leads to global rearrangements of the
extracellular domain as well as channel gating. Yet we lack a clear picture of the molecular events linking
protonation with these observed conformational changes and activation or desensitization. To address this gap
in our knowledge, we will combine electrophysiology with the power of photo-responsive non-canonical amino
acids to test specific molecular hypotheses of protonation-gating coupling. In addition, there has been no
structural data for the ASIC intracellular domains. To address this gap, we will employ a combination of
fluorescence lifetime imaging, as well as patch clamp FRET to map the overall topology and motions of the
intracellular domain using innovative methods of site specific labelling. Finally, despite some reports of ASIC
protein-protein interactions and signal transduction capacity, we lack a clear picture of how ASICs scaffold with
other proteins. We will address this final knowledge gap using targeted protein labeling and downstream analysis
of interactions. Taken together, these proposed experiments will provide new insights into the operation of these
important signaling entities, and may help guide drug development.

## Key facts

- **NIH application ID:** 10204055
- **Project number:** 5R35GM137951-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** David Malcolm MacLean
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10204055

## Citation

> US National Institutes of Health, RePORTER application 10204055, Acid-Sensing Ion Channel gating: Conformations and Consequences (5R35GM137951-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10204055. Licensed CC0.

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