# Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $635,257

## Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of pentameric ligand-gated ion
channels (pLGICs) that mediate fast neurotransmission and are therapeutic targets for various neurological
diseases and disorders. However, no single high-resolution structure has yet been determined for any
full-length nAChRs that contains the extracellular (ECD), transmembrane (TMD), and intracellular (ICD)
domains. Neither X-ray crystallography nor cryo-EM is suitable for resolving structures of the flexible ICD. Lines
of evidence suggest direct interactions between nAChRs and intracellular proteins implicated in synaptic
plasticity and cell signaling pathways, but few molecular details have been revealed due to the lack of
high-resolution structures of the ICD. Here, we propose to determine structures of α7nAChR, which is one of the
most abundant nAChR subtypes in the brain. We have successfully produced functional human full-length
α7nAChR and the TMD+ICD of α7nAChR along with substantial preliminary structural and functional results,
which built a solid foundation for carrying out structural investigations of α7nAChR. Using nuclear magnetic
resonance spectroscopy (NMR) and electron paramagnetic resonance (EPR), we will determine
atomic-resolution structures of the ICD. The ICD structures will be integrated with available structures of the
ECD and TMD, as well as with our newly collected structure restraints to generate structures for full-length
α7nAChR in the resting state. We will elucidate conformational changes underlying α7nAChR desensitization,
which is known to play a significant role in the synaptic control of action-potential transmission. Finally, we will
determine binding modes of α7nAChR networked with intracellular scaffold proteins that affect the distribution of
α7nAChR on the cell surface. The generated structures will provide useful information for developing treatment
strategies for diseases related to α7nAChR.

## Key facts

- **NIH application ID:** 10149981
- **Project number:** 5R01DA046939-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** PEI TANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $635,257
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149981

## Citation

> US National Institutes of Health, RePORTER application 10149981, Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins (5R01DA046939-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10149981. Licensed CC0.

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