# Mechanisms of Neurotransmitter-Gated Ion Channels

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $418,929

## Abstract

The superfamily of pentameric ligand-gated ion channels (pLGICs) is one of the four superfamilies of synaptic
ionotropic receptors present in animals; the other three are the excitatory glutamate receptors, the ATP-gated
cation channels (P2X), and the acid-sensing ion channels (ASIC). Postsynaptic pLGICs mediate fast synaptic
transmission, whereas presynaptic pLGICs modulate the release of other neurotransmitters. In addition, more
recently, some pLGICs have been proposed to be involved in non-neuronal phenomena with the most
compelling evidence suggesting a role for the α7 nicotinic acetylcholine receptor in inflammation. Importantly,
pLGICs are the target of therapeutic drugs (such as benzodiazepines and anesthetics) and recreational drugs
(such as nicotine), and their malfunction is often associated with neurological disease—including neuropathic
pain in diabetic patients, congenital epilepsy, schizophrenia and Alzheimer's disease. Much is known about
the structure and function of these ion channels. However, progress in rational drug design—undoubtedly, a
most intriguing and potentially rewarding application of our basic knowledge—has lagged far behind in part
because our understanding of how structure gives rise to function in pLGICs remains incomplete. Here, we
propose experimental work (electrophysiology, radioligand-binding assays, and direct structural approaches)
and computational work (molecular and Brownian dynamics simulations, and electrostatic calculations) that
will allow us to: 1) Understand the “coupling” between ligand-binding and gating. We will challenge the
prevailing view that the extracellular domain and the transmembrane domain form functionally autonomous
units that need to be “coupled” for the channel to function as a whole; 2) Determine the structure of these
channels in functionally well-defined states and elucidate the effect of the membrane on their conformational
free-energy landscapes; and 3) Characterize the impact of side-chain conformation at the selectivity filter on
cation-versus-anion selectivity. Collectively, these three aims cover the three most fundamental aspects of
ligand-gated ion channels, namely, ligand binding, gating/desensitization, and ion conduction/charge
selectivity.

## Key facts

- **NIH application ID:** 9896852
- **Project number:** 5R01NS042169-16
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** CLAUDIO F GROSMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,929
- **Award type:** 5
- **Project period:** 2003-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896852

## Citation

> US National Institutes of Health, RePORTER application 9896852, Mechanisms of Neurotransmitter-Gated Ion Channels (5R01NS042169-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896852. Licensed CC0.

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