ArticleNature medicine2016
Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.
Article in Nature medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
50 citing papers in PubMed, 89 citations in OpenAlex.
- A first in disease trial of the safety, tolerability, and anti-seizure effects of ES-481 in drug-resistant epilepsy.Epilepsia open · 2026Trial
- A Phase 1, Open-Label, Single Ascending Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of ES-481 After Oral Administration in Healthy Volunteers.European journal of drug metabolism and pharmacokinetics · 2026Trial
- Transmembrane AMPA receptor regulatory protein TARP ɣ-8 is a target of ethanol that regulates self-administration and relapse in mice.Psychopharmacology · 2026Article
- Auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric GluA1/A2 AMPA receptor core.Nature communications · 2026Article
- JNJ-55511118 Stabilizes a Desensitized-like Conformation of γ8-Containing AMPA Receptors through Long-Range Allosteric Modulation.bioRxiv : the preprint server for biology · 2025Article
- AMPA Receptor Modulation in the Treatment of High-Grade Glioma: Translating Good Science into Better Outcomes.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Amplification of the therapeutic potential of AMPA receptor potentiators from the nootropic era to today.Pharmacology, biochemistry, and behavior · 2025Review
- Critical contributions of neuronal subtypes to pediatric drug-resistant focal dysplasia.Frontiers in cell and developmental biology · 2025Article
- Allosteric competition and inhibition in AMPA receptors.Nature structural & molecular biology · 2024Article
- AMPA receptors play an important role in the biological consequences of spinal cord injury: Implications for AMPA receptor modulators for therapeutic benefit.Biochemical pharmacology · 2024Review
- New epilepsy therapies in development.Nature reviews. Drug discovery · 2024Review
- Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs.Cell reports · 2024Article
- Potentiation of AMPA receptors for rapid therapeutic gain in psychiatry has reached a new level of excitement.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- In vitro evaluation of PET radiotracers for imaging synaptic density, the acetylcholine transporter, AMPA-tarp-γ8 and muscarinic M4 receptors in Alzheimer's disease.American journal of nuclear medicine and molecular imaging · 2024Article
- Traumatic brain injury: molecular biomarkers, genetics, secondary consequences, and medical management.Frontiers in neuroscience · 2024Review
- Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice.Nature communications · 2023Article
- Allosteric Competition and Inhibition in AMPA Receptors.bioRxiv : the preprint server for biology · 2023Article
- Negative modulation of AMPA receptors bound to transmembrane AMPA receptor regulatory protein γ-8 blunts the positive reinforcing properties of alcohol and sucrose in a brain region-dependent manner in male mice.Psychopharmacology · 2023Article
- Dysfunction of Glutamatergic Synaptic Transmission in Depression: Focus on AMPA Receptor Trafficking.Biological psychiatry global open science · 2023Review
- Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics.Nature communications · 2023Article
Corrections and comments
- Commented on by
Authors and funding
28 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.
Indexed as
Identifiers
What OpenQuestion holds
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.