Faculty, Staff and Student Publications
Publication Date
7-1-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-60543-5
PMID
40593487
PMCID
PMC12217772
PubMedCentral® Posted Date
7-1-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Memantine is an US Food and Drug Administration (FDA) approved drug that is thought to selectively inhibit NMDA-subtype of ionotropic glutamate receptors (NMDARs). NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine inhibits a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder. Our findings unlock potential exploitation of this site to design more specific drugs targeting CP-AMPARs.
Keywords
Memantine, Receptors, AMPA, Humans, Calcium, Animals, Cryoelectron Microscopy, HEK293 Cells, Receptors, N-Methyl-D-Aspartate, Neurons, Mutation, Excitatory Amino Acid Antagonists
Published Open-Access
yes
Recommended Citation
Carrillo, Elisa; Montaño Romero, Alejandra; Gonzalez, Cuauhtemoc U; et al., "Memantine Inhibits Calcium-Permeable Ampa Receptors" (2025). Faculty, Staff and Student Publications. 4529.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4529
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