# Dynamics of Acid-sensing ion channels

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2023 · $382,493

## Abstract

Project Summary
Acid-sensing ion channels (ASICs) are critical sensors of extracellular pH that contribute to excitability in cells
in both the central and peripheral nervous system. ASICs couple the binding of extracellular protons to the
opening of a sodium selective pore. Preliminary research has suggested that ASICs may be viable targets in
the treatment of pain as well as ischemic events such as stroke. There are 5 ASIC isoforms that give rise to at
least 7 different channel subunits. ASICs form both homo- and heterotrimers and their precise properties are
governed by the channel composition. Research in my lab focuses on the molecular mechanisms underlying
ASIC function and how these channels are fine tuned in neurons. Our first focus is on using cutting-edge
techniques to measure conformational changes in ASICs. Using a FRET approach that replaces the donor
fluorophore with a transition metal ion, we can measure channel dynamics in full-length ASICs in real cells.
With these data, we can build mechanistic models for how ASICs open, close, and desensitize. Despite the
prevalence of heteromeric ASIC complexes in neurons, little is known about the stoichiometry of ASIC
heteromers or the mechanism of heteromer formation. Using a new fluorescence approach called spatial
intensity distribution analysis (SpIDA), we will be able to look at how different ASIC isoforms heteromerize.
Previous work has looked at the stoichiometry of ASIC1a/ASIC2a heteromers, but no other combination has
been studied. Our work will provide the first look at heteromerization between these other ASIC combinations.
In principle, this approach is also compatible with looking at stoichiometry of endogenous receptors in neurons.
We will begin to build our system in that direction. Lastly, we are interested in the macromolecular complexes
that ion channels form. ASICs are known to associate with the Stomatin (STOM) family of proteins. We have
demonstrated that STOM binds to ASIC3 and reduces the current by almost 200-fold. In addition, we have
localized the binding site for STOM on ASIC3 to two critical regions. The first is the distal C-terminus and the
second in the first transmembrane domain (TM1). Extending this work, we plan to use patch clamp
electrophysiology to determine the mechanism of STOM-dependent regulation of ASIC3. In addition, we hope
to extend this work to include other members of the STOM family including Stomatin-like protein 3 (STOML3).
Overall, these studies will provide new insights in two how ASICs function both at the structural and cellular
levels.

## Key facts

- **NIH application ID:** 10618329
- **Project number:** 5R35GM137912-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** John Bankston
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $382,493
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10618329

## Citation

> US National Institutes of Health, RePORTER application 10618329, Dynamics of Acid-sensing ion channels (5R35GM137912-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10618329. Licensed CC0.

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