Cargando…

Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers

Mutations in N-methyl-d-aspartate receptors (NMDAR) subunits have been implicated in a growing number of human neurodevelopmental disorders. Previously, a de novo mutation in GRIN2A, encoding the GluN2A subunit, was identified in a patient with severe epilepsy and developmental delay. This missense...

Descripción completa

Detalles Bibliográficos
Autores principales: Gale, Jenna R., Kosobucki, Gabrielle J., Hartnett-Scott, Karen A., Aizenman, Elias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581401/
https://www.ncbi.nlm.nih.gov/pubmed/34776984
http://dx.doi.org/10.3389/fphar.2021.773455
_version_ 1784596799921586176
author Gale, Jenna R.
Kosobucki, Gabrielle J.
Hartnett-Scott, Karen A.
Aizenman, Elias
author_facet Gale, Jenna R.
Kosobucki, Gabrielle J.
Hartnett-Scott, Karen A.
Aizenman, Elias
author_sort Gale, Jenna R.
collection PubMed
description Mutations in N-methyl-d-aspartate receptors (NMDAR) subunits have been implicated in a growing number of human neurodevelopmental disorders. Previously, a de novo mutation in GRIN2A, encoding the GluN2A subunit, was identified in a patient with severe epilepsy and developmental delay. This missense mutation, which leads to GluN2A-P552R, produces significant dendrotoxicity in transfected rodent cortical neurons, as evidenced by pronounced dendritic blebbing. This injurious process can be prevented by treatment with the NMDA antagonist memantine. Given the increasing use of FDA approved NMDA antagonists to treat patients with GRIN mutations, who may have seizures refractory to traditional anti-epileptic drugs, we investigated whether additional NMDA antagonists were effective in attenuating neurotoxicity associated with GluN2A-P552R expression. Intriguingly, we found that while treatment with memantine can effectively block GluN2A-P552R-mediated dendrotoxicity, treatment with ketamine does not, despite the fact that both drugs work as open NMDAR channel blockers. Interestingly, we found that neurons expressing GluN2A-P552R were more vulnerable to an excitotoxic insult—an effect that, in this case, could be equally rescued by both memantine and ketamine. These findings suggest that GluN2A-P552R induced dendrotoxicity and increased vulnerability to excitotoxic stress are mediated through two distinct mechanisms. The differences between memantine and ketamine in halting GluN2A-P552R dendrotoxicity could not be explained by NMDA antagonist induced changes in MAP or Src kinase activation, previously shown to participate in NMDA-induced excitotoxicity. Our findings strongly suggest that not all NMDA antagonists may be of equal clinical utility in treating GRIN2A-mediated neurological disorders, despite a shared mechanism of action.
format Online
Article
Text
id pubmed-8581401
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-85814012021-11-12 Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers Gale, Jenna R. Kosobucki, Gabrielle J. Hartnett-Scott, Karen A. Aizenman, Elias Front Pharmacol Pharmacology Mutations in N-methyl-d-aspartate receptors (NMDAR) subunits have been implicated in a growing number of human neurodevelopmental disorders. Previously, a de novo mutation in GRIN2A, encoding the GluN2A subunit, was identified in a patient with severe epilepsy and developmental delay. This missense mutation, which leads to GluN2A-P552R, produces significant dendrotoxicity in transfected rodent cortical neurons, as evidenced by pronounced dendritic blebbing. This injurious process can be prevented by treatment with the NMDA antagonist memantine. Given the increasing use of FDA approved NMDA antagonists to treat patients with GRIN mutations, who may have seizures refractory to traditional anti-epileptic drugs, we investigated whether additional NMDA antagonists were effective in attenuating neurotoxicity associated with GluN2A-P552R expression. Intriguingly, we found that while treatment with memantine can effectively block GluN2A-P552R-mediated dendrotoxicity, treatment with ketamine does not, despite the fact that both drugs work as open NMDAR channel blockers. Interestingly, we found that neurons expressing GluN2A-P552R were more vulnerable to an excitotoxic insult—an effect that, in this case, could be equally rescued by both memantine and ketamine. These findings suggest that GluN2A-P552R induced dendrotoxicity and increased vulnerability to excitotoxic stress are mediated through two distinct mechanisms. The differences between memantine and ketamine in halting GluN2A-P552R dendrotoxicity could not be explained by NMDA antagonist induced changes in MAP or Src kinase activation, previously shown to participate in NMDA-induced excitotoxicity. Our findings strongly suggest that not all NMDA antagonists may be of equal clinical utility in treating GRIN2A-mediated neurological disorders, despite a shared mechanism of action. Frontiers Media S.A. 2021-10-28 /pmc/articles/PMC8581401/ /pubmed/34776984 http://dx.doi.org/10.3389/fphar.2021.773455 Text en Copyright © 2021 Gale, Kosobucki, Hartnett-Scott and Aizenman. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Gale, Jenna R.
Kosobucki, Gabrielle J.
Hartnett-Scott, Karen A.
Aizenman, Elias
Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers
title Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers
title_full Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers
title_fullStr Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers
title_full_unstemmed Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers
title_short Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers
title_sort imprecision in precision medicine: differential response of a disease-linked glun2a mutant to nmda channel blockers
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581401/
https://www.ncbi.nlm.nih.gov/pubmed/34776984
http://dx.doi.org/10.3389/fphar.2021.773455
work_keys_str_mv AT galejennar imprecisioninprecisionmedicinedifferentialresponseofadiseaselinkedglun2amutanttonmdachannelblockers
AT kosobuckigabriellej imprecisioninprecisionmedicinedifferentialresponseofadiseaselinkedglun2amutanttonmdachannelblockers
AT hartnettscottkarena imprecisioninprecisionmedicinedifferentialresponseofadiseaselinkedglun2amutanttonmdachannelblockers
AT aizenmanelias imprecisioninprecisionmedicinedifferentialresponseofadiseaselinkedglun2amutanttonmdachannelblockers