ArticleProceedings of the National Academy of Sciences of the United States of America2008
A conserved salt bridge critical for GABA(A) receptor function and loop C dynamics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- A pore-facing glycan constrains GABACommunications biology · 2026Article
- βInternational journal of molecular sciences · 2025Article
- Disentangling the mechanistic role of loop-C capping in Cys-loop receptor activation.Nature communications · 2025Article
- A Pore-Facing Glycan Determines GABAA Receptor Subunit Stoichiometry and Gating Behavior.Research square · 2025Article
- Physical and functional interaction sites in cytoplasmic domains of KCNQ1 and KCNE1 channel subunits.American journal of physiology. Heart and circulatory physiology · 2020Article
- Cadmium opens GluK2 kainate receptors with cysteine substitutions at the M3 helix bundle crossing.The Journal of general physiology · 2019Article
- An intersubunit electrostatic interaction in the GABAThe Journal of biological chemistry · 2018Article
- A triad of residues is functionally transferrable between 5-HTThe Journal of biological chemistry · 2018Article
- The N-Terminal Region of Fibrillin-1 Mediates a Bipartite Interaction with LTBP1.Structure (London, England : 1993) · 2017Article
- Two adjacent phenylalanines in the NMDA receptor GluN2A subunit M3 domain interactively regulate alcohol sensitivity and ion channel gating.Neuropharmacology · 2017Article
- Loop G in the GABAThe Journal of physiology · 2017Article
- A role for loop G in the β1 strand in GABAA receptor activation.The Journal of physiology · 2016Article
- Inter-subunit disulfide locking of the human P2X3 receptor elucidates ectodomain movements associated with channel gating.Purinergic signalling · 2016Article
- Intersubunit interactions at putative sites of ethanol action in the M3 and M4 domains of the NMDA receptor GluN1 and GluN2B subunits.British journal of pharmacology · 2016Article
- A Highly Conserved Salt Bridge Stabilizes the Kinked Conformation of β2,3-Sheet Essential for Channel Function of P2X4 Receptors.The Journal of biological chemistry · 2016Article
- Exploration of the Peptide Recognition of an Amiloride-sensitive FMRFamide Peptide-gated Sodium Channel.The Journal of biological chemistry · 2016Article
- An Electrostatic Funnel in the GABA-Binding Pathway.PLoS computational biology · 2016Article
- Molecular determinants of ATP-sensitive potassium channel MgATPase activity: diabetes risk variants and diazoxide sensitivity.Bioscience reports · 2015Article
- Crystal structure of a human GABAA receptor.Nature · 2014Article
- Intra-subunit flexibility underlies activation and allosteric modulation of neuronal nicotinic acetylcholine receptors.Neuropharmacology · 2014Article
Corrections and comments
- Erratum issued
Authors and funding
2 authors.
Funding
Abstract
Chemical signaling in the brain involves rapid opening and closing of ligand gated ion channels (LGICs). LGICs are allosteric membrane proteins that transition between multiple conformational states (closed, open, and desensitized) in response to ligand binding. While structural models of cys-loop LGICs have been recently developed, our understanding of the protein movements underlying these conformational transitions is limited. Neurotransmitter binding is believed to initiate an inward capping movement of the loop C region of the ligand-binding site, which ultimately triggers channel gating. Here, we identify a critical intrasubunit salt bridge between conserved charged residues (betaE153, betaK196) in the GABA(A) receptor (GABA(A)R) that is involved in regulating loop C position. Charge reversals (E153K, K196E) increased the EC(50) for GABA and for the allosteric activators pentobarbital (PB) and propofol indicating that these residues are critical for channel activation, and charge swap (E153K-K196E) significantly rescued receptor function suggesting a functional electrostatic interaction. Mutant cycle analysis of alanine substitutions indicated that E153 and K196 are energetically coupled. By monitoring disulfide bond formation between cysteines substituted at these positions (E153C-K196C), we probed the mobility of loop C in resting and ligand-bound states. Disulfide bond formation was significantly reduced in the presence of GABA or PB suggesting that agonist activation of the GABA(A)R proceeds via restricting loop C mobility.
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