# Harnessing acid-sensing ion channel toxins for therapeutic purposes

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2022 · $192,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 Generalized anxiety and panic disorder are debilitating disorders resulting in severe social and
economic impact for patients. Antidepressants and benzodiazepines are the current frontline
pharmacological treatments but both medication types come with undesirable side effects, well-
documented compliance issues and/or abuse potential. Acid-sensing ion channels (ASICs) represent
a new drug target and potential treatment avenue for these conditions. ASICs are a family of pH-
activated ion channels found throughout the nervous system, being especially enriched in the
amygdala. Genetic deletion of ASIC genes in mice results in several anxiolytic phenotypes including
greater exploration in open field maze experiments, attenuated freezing in tone-foot shock pairing and
the complete loss of long-term potentiation between synapses in the lateral amygdala. Pharmacological
inhibition of ASICs using the highly selective psalmotoxin1 peptide also produces anxiolytic effects
when injected into rodents. Unfortunately, psalmotoxin1 does not readily cross the blood-brain barrier
and there are currently no high affinity/high selectivity small molecule ASIC drugs. Here we propose to
furnish novel drugs leads using newly described ASIC selective toxins. To do this we will first combine
electrophysiology and high throughput assays to map interactions between human ASIC1a and a
selective toxin. Subsequently, we will use molecular modelling to predict hASIC1a-toxin binding sites.
Finally, we will test these proposed binding sites using electrophysiology and chemical crosslinking.
Together, these aims will identify the binding sites and mechanism of action of high affinity ASIC
selective toxins, providing foundational insight into the channel while expanding the therapeutic
armamentarium. Given the involvement of ASICs in anxiety disorders, and a myriad of other conditions,
such pharmacological advances could have broad health care implications.

## Key facts

- **NIH application ID:** 10322747
- **Project number:** 5R21MH125135-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** David Malcolm MacLean
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2021-01-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322747

## Citation

> US National Institutes of Health, RePORTER application 10322747, Harnessing acid-sensing ion channel toxins for therapeutic purposes (5R21MH125135-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10322747. Licensed CC0.

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