ArticleFrontiers in molecular neuroscience2015
Functional characterization of ivermectin binding sites in α1β2γ2L GABA(A) receptors.
Article in Frontiers in molecular neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 65 citations in OpenAlex.
- Lack of detectable short-term effects of a single dose of ivermectin on the human immune system.Parasites & vectors · 2021Trial
- Neurotropic potential and docking investigations of newly synthesized triazolopyridine and triazolothienopyridine derivatives.RSC advances · 2026Article
- Effects of ivermectin on the activation and desensitization of the human GABAMolecular pharmacology · 2026Article
- Structure of a pH-sensitive pentameric ligand-gated ion channel from the Sarcoptes scabies mite.Nature communications · 2026Article
- Ivermectin exposition during neurulation induces neural tube defects and neuromuscular alterations inFrontiers in pharmacology · 2026Article
- The Nodding syndrome cerebrospinal fluid proteome: a lens into neurodevelopmental failure consistent with environmentally triggeredFrontiers in molecular neuroscience · 2026Article
- Ivermectin toxicosis in a foal: Use of intravenous lipid emulsion therapy.The Canadian veterinary journal = La revue veterinaire canadienne · 2025Article
- Identification and Characterization of Static Craniofacial Defects in Pre-MetamorphicJournal of developmental biology · 2025Article
- Repeated Oral Administration of Ivermectin Belatedly Induces Toxicity and Disrupts the Locomotion and Neuropsychiatric Behavior in Rats.ACS omega · 2025Article
- Impact of ivermectin on nerve regeneration following sciatic injury in mice: the consequences of dietary high fructose.Turkish journal of medical sciences · 2025Article
- New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development.CNS drugs · 2023Review
- Ivermectin modulated cerebral γ-aminobutyric acid (GABA) and reduced the number of chronicJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2023Article
- Pharmacokinetic and pharmacodynamic considerations for treating sarcoptic mange with cross-relevance to Australian wildlife.International journal for parasitology. Drugs and drug resistance · 2023Review
- Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization.ACS chemical neuroscience · 2023Article
- COVID-19 Therapeutics: Use, Mechanism of Action, and Toxicity (Xenobiotics).Journal of medical toxicology : official journal of the American College of Medical Toxicology · 2023Review
- Synthesis and evaluation of the effects of solid lipid nanoparticles of ivermectin and ivermectin on cuprizone-induced demyelination via targeting the TRPA1/NF-kB/GFAP signaling pathway.Iranian journal of basic medical sciences · 2023Article
- Modulation of P2XPhysiological reports · 2022Article
- Article
- Heartworm disease - Overview, intervention, and industry perspective.International journal for parasitology. Drugs and drug resistance · 2021Review
- Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GABAA receptors (GABAARs) are the major inhibitory neurotransmitter receptors in the brain and are therapeutic targets for many indications including sedation, anesthesia and anxiolysis. There is, however, considerable scope for the development of new therapeutics with improved beneficial effects and reduced side-effect profiles. The anthelminthic drug, ivermectin, activates the GABAAR although its binding site is not known. The molecular site of action of ivermectin has, however, been defined by crystallography in the homologous glutamate-gated chloride channel. Resolving the molecular mechanisms of ivermectin binding to α1β2γ2L GABAARs may provide insights into the design of improved therapeutics. Given that ivermectin binds to subunit interfaces, we sought to define (1) which subunit interface sites it binds to, (2) whether these sites are equivalent in terms of ivermectin sensitivity or efficacy, and (3) how many must be occupied for maximal efficacy. Our approach involved precluding ivermectin from binding to particular interfaces by introducing bulky M3 domain 36'F sidechains to the "+" side of those interfaces. We thereby demonstrated that ivermectin produces irreversible channel activation only when it binds to the single γ2L-β2 interface site. When it binds to α1-β2 sites it elicits potentiation of GABA-gated currents but has no irreversible activating effect. Ivermectin cannot bind to the β2-α1 interface site due to its endogenous bulky 36' methionine. Replacing this with an alanine creates a functional site at this interface, but surprisingly it is inhibitory. Molecular docking simulations reveal that the γ2L-β2 interface forms more contacts with ivermectin than the other interfaces, possibly explaining why ivermectin appears to bind irreversibly at this interface. This study demonstrates unexpectedly stark pharmacological differences among GABAAR ivermectin binding sites.
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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.