# Structural studies of heteromeric nicotinic acetylcholine receptors

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $364,500

## Abstract

Abstract
 Neuronal nicotinic acetylcholine receptors are essential therapeutic targets for addiction, mental health
and neurodegenerative disorders. These pentameric ligand-gated ion channels are the prototypical members
of the Cys-loop receptor superfamily, which mediate fast neurotransmission throughout the central and
peripheral nervous systems. Here we propose to determine high-resolution structures of two representative
neuronal nicotinic receptor subtypes. Structural analysis of nicotinic receptors has been hampered by the
challenges of recombinant expression of eukaryotic membrane proteins. These proteins typically express at
low levels and are unstable after purification. Furthermore, most nicotinic receptors are obligate heteromers
and in many cases these heteromers can assemble as pentamers with different ratios of subunits. This
complication of mixed stoichiometry is present among all Cys-loop receptor families but is best characterized in
the nicotinic receptors. The structural heterogeneity results in physiologically important, finely tuned
pharmacological and channel properties. In Aim 1, we propose to develop methods for expression and
purification of these receptors that can assemble in multiple stoichiometries. In Aims 2 and 3 we propose to
apply these approaches to determine structures of two heteromeric nicotinic receptors in physiologically-
relevant and functionally-distinct alternate stoichiometries. The individual receptor structures will provide key
insights into the structural underpinnings of ion permeation and ligand recognition. Comparison of the
structures of the two receptors, and of alternative stoichiometries of the same receptor, will provide a reliable
structural foundation for understanding the distinctive biophysical and pharmacological properties of each
receptor subunit combination.

## Key facts

- **NIH application ID:** 9948608
- **Project number:** 5R01DA042072-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ryan E Hibbs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948608

## Citation

> US National Institutes of Health, RePORTER application 9948608, Structural studies of heteromeric nicotinic acetylcholine receptors (5R01DA042072-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948608. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*