# Cryo-EM Studies of the Structure and Allosteric Mechanisms of Heteromeric Glycine Receptor

> **NIH NIH F32** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $69,802

## Abstract

Project Summary and Abstract: Glycine receptors (GlyR) are the primary mediators of synaptic
neural inhibition in the brainstem and spinal cord. They are essential to many physiological
processes and intriguing, yet untapped, therapeutic targets. The overall goal of this project is to
understand the processes that control GlyR activity and provide a template for therapeutic design.
GlyR is a pentameric ligand-gated ion channel expressed in homomeric and heteromeric forms.
Heteromeric GlyR is essential for synaptic activity as it alone can bind the synaptic anchoring
protein gephryin. This proposal uses cryogenic electron microscopy (cryo-EM), electrophysiology
and electron paramagnetic resonance (EPR) to achieve mechanistic understanding of
heteromeric GlyR bound to gephryin. This will build upon past cryo-EM studies of homomeric
GlyR. The specific aims of this proposal are: First, to characterize subunit-specific structures in
hetero-GlyR known to regulate subunit composition, ion conduction and intracellular regulation.
Second, study conformational coupling between the neurotransmitter binding pocket and channel
gate. Third, explore the allosteric effects of ligands that bind within the transmembrane domain of
hetero-GlyR. The applicant has shown significant progress by expressing and purifying
heteromeric GlyR and performing preliminary cryo-EM studies resulting in a 2.25-2.5 Å cryo-EM
map. In accomplishing this project, the applicant will receive training in membrane protein
biochemistry, cryo-EM, electrophysiology and EPR. This project will take place in Sudha
Chakrapani’s lab at Case Western Reserve University. This lab has made significant recent
contributions to the field with cryo-EM studies of homomeric GlyR and other ligand-gated ion
channels. Available resources include a cryo-EM facility with a Titan Krios microscope and lab-
dedicated electrophysiology rigs. Several members of the lab have extensive experience in cryo-
EM, electrophysiology and/or EPR providing an excellent training environment.

## Key facts

- **NIH application ID:** 10388533
- **Project number:** 1F32GM142233-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Eric D. Gibbs
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $69,802
- **Award type:** 1
- **Project period:** 2022-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388533

## Citation

> US National Institutes of Health, RePORTER application 10388533, Cryo-EM Studies of the Structure and Allosteric Mechanisms of Heteromeric Glycine Receptor (1F32GM142233-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10388533. Licensed CC0.

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