ArticleThe Journal of biological chemistry2011
Discrete M3-M4 intracellular loop subdomains control specific aspects of γ-aminobutyric acid type A receptor function.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 22 citations in OpenAlex.
- Mechanism of human α3β GlyR regulation by intracellular M3/M4 loop phosphorylation and 2,6-di-tert-butylphenol interaction.Nature communications · 2025Article
- Structure-function Studies of GABA (A) Receptors and Related computer-aided Studies.Journal of molecular neuroscience : MN · 2023Review
- Analyzing the mechanisms that facilitate the subtype-specific assembly ofFrontiers in molecular neuroscience · 2022Article
- A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Increased Dendritic Branching of and Reduced δ-GABAFrontiers in cellular neuroscience · 2020Article
- Inhibitory Synapse Formation at the Axon Initial Segment.Frontiers in molecular neuroscience · 2019Article
- Cell surface expression of homomeric GABAThe Journal of biological chemistry · 2018Article
- Expression and purification of a functional heteromeric GABAA receptor for structural studies.PloS one · 2018Article
- A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation.Neuropharmacology · 2017Article
- Instant Integrated Ultradeep Quantitative-structural Membrane Proteomics Discovered Post-translational Modification Signatures for Human Cys-loop Receptor Subunit Bias.Molecular & cellular proteomics : MCP · 2016Article
- Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses.Pharmacological research · 2015Review
- Evidence for α-helices in the large intracellular domain mediating modulation of the α1-glycine receptor by ethanol and Gβγ.The Journal of pharmacology and experimental therapeutics · 2015Article
- An internally modulated, thermostable, pH-sensitive Cys loop receptor from the hydrothermal vent worm Alvinella pompejana.The Journal of biological chemistry · 2014Article
- Some insights into the binding mechanism of the GABAA receptor: a combined docking and MM-GBSA study.Journal of molecular modeling · 2013Article
- An outline of desensitization in pentameric ligand-gated ion channel receptors.Cellular and molecular life sciences : CMLS · 2013Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The GABA type A receptor (GABA(A)R) is a member of the pentameric ligand gated ion channel (pLGIC) family that mediates ionotropic neurotransmission. Residues in the intracellular loop domain (ILD) have recently been shown to define part of the ion permeation pathway in several closely related members of the pentameric ligand gated ion channel family. In this study, we investigated the role the ILD of the GABA(A)R α1 subunit plays in channel function. Deletion of the α1 ILD resulted in a significant increase in GABA EC(50) and maximal current amplitude, suggesting that the ILD must be intact for proper receptor function. To test this hypothesis, we conducted a mutagenic screen of all amino acids harboring ionizable side chains within this domain to investigate the contribution of individual charged residues to ion permeation. Using macroscopic and single channel voltage-clamp recording techniques, we found that mutations within a subdomain of the α1 ILD near M3 altered GABA apparent affinity; interestingly, α1(K312E) exhibited reduced partial agonist efficacy. We introduced point mutations near M4, including α1(K383E) and α1(K384E), that enhanced receptor desensitization. Mutation of 5 charged residues within a 39-residue span contiguous with M4 reduced relative anion permeability of the channel and may represent a weak intracellular selectivity filter. Within this subdomain, the α1(K378E) mutation induced a significant reduction in single channel conductance, consistent with our hypothesis that the GABA(A)R α1 ILD contributes directly to the permeation pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.