ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Allosteric modulation of an excitatory amino acid transporter: the subtype-selective inhibitor UCPH-101 exerts sustained inhibition of EAAT1 through an intramonomeric site in the trimerization domain.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 65 citations in OpenAlex.
- Synergistic apoptotic induction in acute lymphoblastic leukemia cells: exploring the role of EAAT1 inhibition by UCPH-101 in combination with asparaginase.Molecular biology reports · 2026Article
- Overactive EAAT1 ClActa neuropathologica communications · 2026Article
- Structure-guided optimization of SLC1A1/EAAT3-selective inhibitors targeting renal cancer metabolism.The EMBO journal · 2026Article
- The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.PloS one · 2026Article
- Brain pericytes upregulate glutamate uptake by astrocytesIBRO neuroscience reports · 2025Article
- Recent advances in ASCT2 inhibitors: ligand design and therapeutic applications.Future medicinal chemistry · 2025Review
- Review
- Glutamate Spillover Dynamically Strengthens Gabaergic Synaptic Inhibition of the Hypothalamic Paraventricular Nucleus.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- FN1 mediated activation of aspartate metabolism promotes the progression of triple-negative and luminal a breast cancer.Breast cancer research and treatment · 2023Article
- Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity.International journal of molecular sciences · 2023Article
- Article
- Molecular insights into disease-associated glutamate transporter (EAAT1 /Frontiers in molecular biosciences · 2023Article
- Elevation of Extracellular Glutamate by Blockade of Astrocyte Glutamate Transporters Inhibits Cocaine Reinforcement in Rats via a NMDA-GluN2B Receptor Mechanism.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Impedance-Based Phenotypic Readout of Transporter Function: A Case for Glutamate Transporters.Frontiers in pharmacology · 2022Article
- Article
- Structural Aspects of Photopharmacology: Insight into the Binding of Photoswitchable and Photocaged Inhibitors to the Glutamate Transporter Homologue.Journal of the American Chemical Society · 2021Article
- Glial Chloride Homeostasis Under Transient Ischemic Stress.Frontiers in cellular neuroscience · 2021Article
- Cellular Physiology and Pathophysiology of EAAT Anion Channels.Frontiers in cellular neuroscience · 2021Review
- Potential Mechanism of Cellular Uptake of the Excitotoxin Quinolinic Acid in Primary Human Neurons.Molecular neurobiology · 2021Article
- Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy.Trends in pharmacological sciences · 2020Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In the present study, the mechanism of action and molecular basis for the activity of the first class of selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rodent ortholog GLAST are elucidated. The previously reported specificity of UCPH-101 and UCPH-102 for EAAT1 over EAAT2 and EAAT3 is demonstrated to extend to the EAAT4 and EAAT5 subtypes as well. Interestingly, brief exposure to UCPH-101 induces a long-lasting inactive state of EAAT1, whereas the inhibition exerted by closely related analogs is substantially more reversible in nature. In agreement with this, the kinetic properties of UCPH-101 unblocking of the transporter are considerably slower than those of UCPH-102. UCPH-101 exhibits noncompetitive inhibition of EAAT1, and its binding site in GLAST has been delineated in an elaborate mutagenesis study. Substitutions of several residues in TM3, TM4c, and TM7a of GLAST have detrimental effects on the inhibitory potency and/or efficacy of UCPH-101 while not affecting the pharmacological properties of (S)-glutamate or the competitive EAAT inhibitor TBOA significantly. Hence, UCPH-101 is proposed to target a predominantly hydrophobic crevice in the "trimerization domain" of the GLAST monomer, and the inhibitor is demonstrated to inhibit the uptake through the monomer that it binds to exclusively and not to affect substrate translocation through the other monomers in the GLAST trimer. The allosteric mode of UCPH-101 inhibition underlines the functional importance of the trimerization domain of the EAAT and demonstrates the feasibility of modulating transporter function through ligand binding to regions distant from its "transport domain."
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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.