# Structural Foundations of Nicotinic Acetylcholine Receptor Function

> **NIH NIH F31** · MAYO CLINIC ROCHESTER · 2020 · $45,520

## Abstract

Project Summary
Throughout the nervous system, nicotinic acetylcholine receptors (nAChRs) are tasked with facilitating rapid
communication between cells by converting a chemical signal to an electrical impulse. When acetylcholine is
released into the synapse, membrane bound nAChRs bind the small organic molecule and open the receptor
pore in response, allowing a selected subset of extracellular ions to flow into the cell. Disruption of normal
nAChR function can result in severe and debilitating neurological diseases, such as myasthenic syndromes
and certain epileptic disorders. A major emphasis of our laboratory is uncovering how the three dimensional
structure of nAChRs allows them to perform their physiologic task. For we assert that a basic understanding of
how receptor structure endows function will allow us to more effectively intervene in the setting of nAChR-
driven neurological diseases. Recently determined high-resolution nAChR structures reveal a conserved
charge-charge interaction between pore-lining and peripheral α-helices that was not apparent in the first
published nAChR structures. This proposal seeks to determine the function of this conserved interaction by
pairing precise modifications to receptor structure with state-of-the-art single channel electrophysiology. My
preliminary work shows that this transmembrane charge-charge interaction is critical for the stability of the
open state of the receptor and for the uniform open channel current inherent to nAChRs. Therefore I
hypothesize that a universally conserved charge-charge interaction between pore-lining and peripheral
transmembrane a-helices enhances gating efficiency and facilitates uniform ion permeation in nAChRs. To test
this hypothesis I will break the pore-peripheral charge-charge interaction using mutagenesis and probe the
function of resultant receptors using single channel electrophysiology. First, I will determine the ion permeation
characteristics of the mutant and wild-type receptors (aim 1). Then I will determine the gating energetics of wild
type and mutant receptors (aim 2). Accomplishing these two aims will help provide the mechanistic framework
required to understand and treat diseases driven by abnormal nAChR function.

## Key facts

- **NIH application ID:** 10024224
- **Project number:** 5F31NS115358-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** John R Strikwerda
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-30 → 2021-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024224

## Citation

> US National Institutes of Health, RePORTER application 10024224, Structural Foundations of Nicotinic Acetylcholine Receptor Function (5F31NS115358-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10024224. Licensed CC0.

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