GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors
Open accessAbstract
De novo gain of function mutations in GRIN2B encoding the GluN2B subunit of the N -methyl- d -aspartate (NMDA) receptor have been linked with epileptic encephalopathies, including infantile spasms. We investigated the effects of radiprodil, a selective GluN2B negative allosteric modulator and other non-selective NMDA receptor inhibitors on glutamate currents mediated by NMDA receptors containing mutated GluN2B subunits. The experiments were performed in Xenopus oocytes co-injected with the following human mRNAs: GRIN1/GRIN2B, GRIN1/GRIN2B-R540H, GRIN1/GRIN2B-N615I and GRIN1/GRIN2B-V618G. Glutamate displayed slightly increased potency in the R540H variant, but not in N615I and V618G variants. However, the inhibition by Mg 2+ was completely abolished in N615I and V618G variants. In fact, Mg 2+ enhanced glutamate responses in those variants. The potency of radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants. Additionally, in the Mg 2+ insensitive variants, radiprodil blocked glutamate-activated currents with the same potency as in the absence of Mg 2+ . The gain of function observed in the reported GRIN2B variants could be a key pathophysiological factor leading to neuronal hyper-excitability in epileptic encephalopathies. The GluN2B-selective inhibitor radiprodil fully retained its pharmacological profile under these conditions, while other non-selective NMDA receptor antagonists lost their potency. Consequently, our data suggest that radiprodil may be a valuable therapeutic option for treatment of pediatric epileptic encephalopathies associated with GRIN2B mutations.
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Trials targeting specific channelopathies are being developed: potent selective potassium channel openers, retigabine and ezogabine, for KCNQ2-DEE; a powerful, highly selective Nav1.6 inhibitor for SCN8A-DEE, and a selective GluN2B negative allosteric modulator, radiprodil, for GRIN2B GOF DEE.
“Trials targeting specific channelopathies are being developed: potent selective potassium channel openers, retigabine and ezogabine, for KCNQ2-DEE; a powerful, highly selective Nav1.6 inhibitor for SCN8A-DEE 186 , and a selective GluN2B negative allosteric modulator, radiprodil, for GRIN2B GOF DEE 187 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [187]
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Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels
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- Authors
- Mullier, B., Wolff, C., Sands, Z. A., Ghisdal, P., Muglia, P., Kaminski, R. M., & André, V. M.
- Affiliations
- UCB Pharma (Belgium) (BE)
- Corresponding author
- André, Véronique Marie
- ORCID
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 123
- Pages
- 322-331
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2618794745
- Cited by
- 65
- References
- 59
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 10 · 2023: 4 · 2022: 5 · 2021: 12 · 2020: 7 · 2019: 7 · 2018: 1 · 2017: 3
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropharmacology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- UCB BioPharma sprl
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- NR2B subunit, GluN2B, NMDA receptor, negative allosteric modulators, gain-of-function mutations, infantile spasms, epileptic encephalopathy, magnesium sensitivity, NMDA receptor antagonists, neuronal hyperexcitability, pediatric epilepsy treatment
- MeSH terms
- Gain of Function Mutation, Acetamides, Animals, Cations, Divalent, Humans, Magnesium, Models, Molecular, Nerve Tissue Proteins, Oocytes, Piperidines, RNA, Messenger, Xenopus, Receptors, N-Methyl-D-Aspartate, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Glutamic Acid
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