# Lipid Modulation of Ligand-Gated Ion Channels

> **NIH NIH R35** · WASHINGTON UNIVERSITY · 2024 · $393,750

## Abstract

Project Summary/Abstract
Pentameric ligand-gated ion channels (pLGICs) mediate synaptic transmission and are the targets of many
neuroactive drugs, which are allosteric modulators of pLGIC activity. Endogenous lipids including phospholipids,
fatty acids and steroids are also allosteric modulators of pLGICs, and the effects of these lipids are fundamental
to our understanding of pLGIC biology and regulation. The long-term goal of this project is to understand the
molecular mechanisms by which lipids modulate pLGICs. We have developed innovative biophysical and
biochemical techniques to examine lipid binding and modulation in the model pLGIC, Erwinia chrysanthemi
ligand-gated ion channel (ELIC), including native ion mobility mass spectrometry (MS), functional analysis in
model membranes, and covalent modification/photolabeling. Using these techniques, we discovered that the
anionic phospholipid, 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), directly binds to ELIC and modulates
channel gating by stabilizing the open relative to the desensitized state. We now propose to investigate the
mechanisms of phospholipid, fatty acid and steroid modulation of two model pLGICs, ELIC and GLIC
(Gloeobacter ligand-gated ion channel), with a focus on elucidating the specificity and sites of interaction, and
the effects of lipid binding. The overall vision of this research program is to develop a detailed structural model
of lipid modulation of pLGICs that encompasses the potential diversity of mechanisms present in different
pLGICs.

## Key facts

- **NIH application ID:** 10870003
- **Project number:** 5R35GM137957-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Wayland Wing-Lun Cheng
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10870003

## Citation

> US National Institutes of Health, RePORTER application 10870003, Lipid Modulation of Ligand-Gated Ion Channels (5R35GM137957-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10870003. Licensed CC0.

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