# Structure and Function of Pentameric Ligand-Gated Ion Channels

> **NIH NIH R35** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $41,865

## Abstract

Project Summary/Abstract
The overarching goal of the proposal is to determine the structural basis for allosteric mechanisms governing
gating and modulation in pentameric ligand-gated ion channels (pLGIC). The pLGIC superfamily governs crucial
physiological processes such as gastrointestinal functions, motor functions, and pain transmission. Aberrant
channel functions are implicated in mood disorders, addiction, chronic pain, and cancer. Currently used
therapeutic strategies suffer from our limited knowledge of the molecular details of pLGIC function, the origin of
their functional diversity, and the downstream signaling events. Using single-particle cryo-EM, we recently
solved structures of the full-length serotonin receptor (5HT3AR), a cationic pLGIC, in the resting state and two
serotonin-activated conformations. Building on this technical advancement and further biochemical
optimization, we aim to determine the conformational changes underlying gating and lipid modulation in the full-
length homomeric and heteromeric receptors within the cationic 5-HT3R and anionic glycine receptor (GlyR)
subfamilies. To achieve these goals we will use an approach that combines multidisciplinary techniques,
including cryo-EM, pulsed-EPR, and electrophysiology. Specifically, we will determine high-resolution
snapshots of pLGIC in multiple functional states, in modulator-bound conformations, in the presence of
membrane lipid constituents, and in complex with intracellular-binding proteins. These structures will be
validated and complemented with protein dynamic studies in a membrane environment and extensive functional
analysis. Taken together, our proposed work is expected to provide molecular blueprints of the channel in
physiologically relevant conformations for therapeutic targeting and unravel the molecular mechanisms
underlying channel function. These findings will, in turn, pave the way for design of novel therapeutic agents
that are safer and more effective.

## Key facts

- **NIH application ID:** 10388455
- **Project number:** 3R35GM134896-02S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Sudha Chakrapani
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,865
- **Award type:** 3
- **Project period:** 2020-01-21 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388455

## Citation

> US National Institutes of Health, RePORTER application 10388455, Structure and Function of Pentameric Ligand-Gated Ion Channels (3R35GM134896-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10388455. Licensed CC0.

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