# Structural basis of nicotinic acetylcholine receptor gating and toxin inhibition

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $698,278

## Abstract

Nicotinic acetylcholine receptors are therapeutic targets for neurodegenerative disorders, addiction, and mental
illness. These pentameric ligand-gated ion channels are prototypical members of the Cys-loop receptor
superfamily, which mediate fast neurotransmission throughout the central and peripheral nervous systems.
Fundamental questions about nicotinic receptor biophysics and pharmacology remain, due in large part to the
limited high-resolution structural information. We propose to determine high-resolution structures of two
archetypal nicotinic receptor subtypes using single particle cryo-electron microscopy and investigate structure-
based mechanistic hypotheses using molecular dynamics simulations and electrophysiology. Our first target is
the muscle-type nicotinic receptor, the founding member of the pentameric receptor superfamily. Mutations in
the channel, as well as autoimmune antibodies to the receptor, cause myasthenic syndromes. Our second
target is the human α7 nicotinic receptor. α7 is exceptional among nicotinic receptors in several ways: it
assembles physiologically as a homopentamer, it is expressed abundantly in the brain but also in non-
electrically excitable cell types, it has a high permeability to Ca2+, and it desensitizes in microseconds. The
receptor is a target in neurodegenerative disease, addiction and inflammation. We propose to use single
particle cryo-electron microscopy combined with mutagenesis, electrophysiology and molecular dynamics
simulations to elucidate mechanisms of channel activation, ligand recognition and ion permeation in these two
distinctinctive nicotinic receptor subtypes to define general mechanisms and idiosyncratic properties.

## Key facts

- **NIH application ID:** 10848770
- **Project number:** 7R01NS120496-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ryan E Hibbs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $698,278
- **Award type:** 7
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848770

## Citation

> US National Institutes of Health, RePORTER application 10848770, Structural basis of nicotinic acetylcholine receptor gating and toxin inhibition (7R01NS120496-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848770. Licensed CC0.

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