# Desensitization of Nicotinic Acetylcholine Receptors

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $537,742

## Abstract

Nicotinic acetylcholine receptors (AChRs) at the nerve-muscle synapse enter and recover from
D(esensitized) states that remain inactive in the continuous presence of neurotransmitter.
Receptor desensitization down-regulates cell responses and encodes long-term activity patterns.
Our goal is to understand the AChR desensitization process at a molecular level. The essential
problem of how D states are connected to C(losed) and O(pen) gating states remains unsolved.
We will investigate two hypotheses: i) D, O and C are connected in a closed cycle and ii) D is not
connected either to C or O but rather to a short-lived gating intermediate state. We will test the
second hypothesis experimentally by using mutations and voltage to shift the point of
bifurcation between gating and desensitization conformational-change pathways, towards C to
produce openings upon recovery or towards O to prevent openings. Many amino acids change
structure during the AChR gating and desensitization transitions, and each of these microscopic
rearrangements has an associated and mostly-local free energy change. We will measure these
energy changes in desensitization at two regions in the AChR transmembrane domain: i) a
proline kink in M1 and ii) the hydrophobic M2 gate. Despite intensive investigation, the
molecular basis of AChR desensitization has remained obscure since the process was first
described 60 years ago. The experiments in this proposal will fill this substantial gap in our
understanding of receptor operation.

## Key facts

- **NIH application ID:** 9920740
- **Project number:** 5R01GM121463-04
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Anthony L Auerbach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,742
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920740

## Citation

> US National Institutes of Health, RePORTER application 9920740, Desensitization of Nicotinic Acetylcholine Receptors (5R01GM121463-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9920740. Licensed CC0.

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