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Journal of Neurochemistry - 2025 - Fraser - Milestone Review Unlocking the Proteomics of Glycine Receptor Complexes2.56 MB
Published VersionCC BY V4.0, Open Access
Journal article
Milestone Review: Unlocking the Proteomics of Glycine Receptor Complexes
Journal of Neurochemistry, Vol.169(4), pp.1-23
2025
PMCID: PMC12032442
PMID: 40285371
Appears in UniSC Supported Open Access Outputs
Abstract
Glycine receptors (GlyRs) are typically known for mediating inhibitory synaptic transmission within the spinal cord and brainstem, but they also have key roles in embryonic brain development, learning/memory, inflammatory pain sensitization, and rhythmic breathing. GlyR dysfunction has been implicated in multiple neurological disease states, including startle disease (GlyR α1β) and neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD), intellectual disability (ID), developmental delay (DD) and epilepsy (GlyR α2). However, GlyRs do not operate in isolation but depend upon stable and transient protein–protein interactions (PPIs) that influence synaptic localization, homeostasis, signaling pathways, and receptor function. Despite the affinity purification of GlyRs using the antagonist strychnine over four decades ago, we still have much to learn about native GlyR stoichiometry and accessory proteins. In contrast to other neurotransmitter receptors, < 20 potential GlyR interactors have been identified to date. These include some well-known proteins that are vital to inhibitory synapse function, such as the postsynaptic scaffolding protein gephyrin and the RhoGEF collybistin. However, the majority of known interactors either bind to the GlyR α1 and β subunits, or the binding partner in the GlyR complex is unknown. Several potential GlyR interactors are not found at inhibitory synapses and/or have no clear functional role. Moreover, other GlyR interactors are secondary interactors that bind indirectly, for example, via gephyrin. In this review, we provide a critical evaluation of known GlyR interacting proteins and methodological limitations to date. We also provide a road map for the use of innovative and emerging interaction proteomic techniques that will unlock the GlyR interactome. With the emergence of disease-associated missense mutations in the α1, α2 and β subunit intracellular domains in startle disease and NDDs, understanding the identity and roles of GlyR accessory proteins is vital in understanding GlyR function and dysfunction in health and disease.
Details
- Title
- Milestone Review: Unlocking the Proteomics of Glycine Receptor Complexes
- Authors
- Sean Fraser - University of the Sunshine Coast, Queensland, School of Health - BiomedicineRemco V Klaassen - Vrije Universiteit AmsterdamCarmen Villmann - Universitätsklinikum WürzburgAugust B Smit - Vrije Universiteit AmsterdamRobert Harvey (Corresponding Author) - University of the Sunshine Coast, Queensland, School of Health
- Publication details
- Journal of Neurochemistry, Vol.169(4), pp.1-23
- Publisher
- Wiley-Blackwell Publishing Ltd.
- Date published
- 2025
- DOI
- 10.1111/jnc.70061
- ISSN
- 1471-4159; 0022-3042
- PMID
- 40285371; PMC12032442
- Copyright note
- © 2025 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Data Availability
- Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
- Grants
- Microproteins: from invisibility to relevance in neuroscience and cancer, 0980029932, University of the Sunshine Coast (Australia, Sunshine Coast) - UniSC
- Grant note
- Deutsche Forschungsgemeinschaft. Grant Number: VI586
- Organisation Unit
- School of Health - Biomedicine; School of Health
- Language
- English
- Record Identifier
- 991122352102621
- Output Type
- Journal article
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- Biochemistry & Molecular Biology
- Neurosciences
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