ArticlePLoS biology2019
Multiple functional neurosteroid binding sites on GABAA receptors.
Article in PLoS biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 103 citations in OpenAlex.
- Structural dynamics of kappa opioid receptor interactions with β-arrestin 1.Nature communications · 2026Article
- Activation of the human β3 GABABiochemical pharmacology · 2026Article
- Pregnanolone Glutamate: A Dual-Fate Delivery System for Neuroactive Steroids in Perinatal Focal Cerebral Ischemia.International journal of molecular sciences · 2026Article
- Structure-Function Studies of Pentameric Ligand-Gated Ion Channels: Combining Experimental and Computational Approaches.Advances in experimental medicine and biology · 2026Review
- Golexanolone Attenuates Neuroinflammation, Fatigue, and Cognitive and Motor Impairment in Diverse Neuroinflammatory Disorders.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Neurosteroids and translocator protein 18 kDa (TSPO) ligands as novel treatment options in depression.European archives of psychiatry and clinical neuroscience · 2025Review
- Neuroactive Steroids as Novel Promising Drugs in Therapy of Postpartum Depression-Focus on Zuranolone.International journal of molecular sciences · 2025Review
- From neurotoxicity to neuroprotection: Rethinking GABACell biology and toxicology · 2025Review
- Single cell resolution of neurosteroidogenesis in the murine brain: intermediary biosynthesis.The Journal of endocrinology · 2025Article
- Interaction Between Allopregnanolone and Amiloride Binding Sites on the GABACell biochemistry and biophysics · 2025Article
- New directions in neurosteroid therapeutics in neuropsychiatry.Neuroscience and biobehavioral reviews · 2025Review
- Premenstrual dysphoric disorder as a potential predisposing factor for Alzheimer's disease: a review.Frontiers in endocrinology · 2025Review
- Neurosteroids: a lifelong impact on brain health.Frontiers in behavioral neuroscience · 2025Review
- Synthesis and evaluation of photoaffinity labeling reagents for identifying binding sites of sulfated neurosteroids on NMDA and GABARSC advances · 2024Article
- Direct measurements of neurosteroid binding to specific sites on GABABritish journal of pharmacology · 2024Article
- Inhibitory Actions of Potentiating Neuroactive Steroids in the Human α1β3γ2L γ-Aminobutyric Acid Type A Receptor.Molecular pharmacology · 2024Article
- Neurosteroids and their potential as a safer class of general anesthetics.Journal of anesthesia · 2024Review
- Neurosteroid Binding and Actions on GABAJuntendo Iji zasshi = Juntendo medical journal · 2024Review
- Neurosteroids: mechanistic considerations and clinical prospects.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Review
- Established and emerging GABAFrontiers in pharmacology · 2024Review
6 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While gamma amino-butyric acid Type A (GABAA) receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry (MS), we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1β3 GABAA receptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α1 (labeled residues α1-N408, Y415) and β3 (labeled residue β3-Y442) subunits, adjacent to the extracellular domains (ECDs). An intersubunit site (labeled residues β3-L294 and G308) in the interface between the β3(+) and α1(-) subunits of the GABAA receptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABAA receptors. Electrophysiological studies of receptors with mutations based on these predictions (α1-V227W, N408A/Y411F, and Q242L) indicate that both the α1 intrasubunit and β3-α1 intersubunit sites are critical for neurosteroid action.
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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.