# Structure-function of the α4β2 nicotinic acetylcholine receptor in a lipidic environment

> **NIH NIH F32** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $69,306

## Abstract

Project summary (1-2 para):
 Nicotinic acetylcholine receptors are ligand-gated ion channels that are widely expressed throughout the
central and peripheral nervous systems. The α4β2 nicotinic receptor is the most abundant subtype in the brain
and is linked to nicotine addiction and neurological disorders including Alzheimer's and Parkinson's diseases.
Expression of the α4β2 receptor is upregulated by chronic exposure to nicotine in vitro and in the brains of
smokers compared to that of non-smokers. Accordingly, there have been extensive efforts to develop small
molecules to reduce tobacco addiction by targeting this receptor type, but these efforts are hampered by the
limited amount of structural information for nicotinic receptors. Atomic structures of a desensitized-state nicotinic
receptor in detergent obtained by X-ray crystallography and Cryo-EM are known, but high-resolution structures
in a physiologically relevant lipidic environment remain unresolved. Moreover, we lack structural information for
this receptor in the different states along the gating cycle. Here I propose to first identify combinations of lipids
that support robust channel function using electrophysiological approaches. In parallel I will optimize sample
preparation for the α4β2 nicotinic receptor in lipidic nanodiscs, leveraging the information from the functional
studies in defined lipidic environments. I will use these preparations to obtain high resolution structural
information for the α4β2 nicotinic receptor in distinct conformational states, in an experimental condition tied
directly to a physiological preparation. Structural information for the receptor in a membrane and in different
conformational states will provide touchstones for understanding allosteric gating of these receptors and
templates for development of state-selective pharmacological tools and therapeutics.

## Key facts

- **NIH application ID:** 9982041
- **Project number:** 5F32DA047848-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Guipeun Kang
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2019-06-07 → 2022-06-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982041

## Citation

> US National Institutes of Health, RePORTER application 9982041, Structure-function of the α4β2 nicotinic acetylcholine receptor in a lipidic environment (5F32DA047848-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982041. Licensed CC0.

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