9E4Z

GluA2-gamma2 complex bound glutamate and cyclothiazide

Summary for 9E4Z

• Entry DOI: 10.2210/pdb9e4z/pdb
• EMDB information: 47521
• Descriptor: Isoform Flip of Glutamate receptor 2, Voltage-dependent calcium channel gamma-2 subunit, GLUTAMIC ACID, ... (4 entities in total)
• Functional Keywords: ligand-gated ion channel, ionotropic glutamate receptor, ampa receptor, ion channel, transport protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 8
• Total formula weight: 458052.72

Authors

Montano Romero, A.,Carrillo, E.,Jayaraman, V.,Twomey, E.C. (deposition date: 2024-10-25, release date: 2025-06-18, Last modification date: 2025-07-16)

Primary citation

Carrillo, E.,Montano Romero, A.,Gonzalez, C.U.,Turcu, A.L.,Vazquez, S.,Twomey, E.C.,Jayaraman, V.
Memantine inhibits calcium-permeable AMPA receptors.
Nat Commun, 16:5576-5576, 2025

PubMed 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.

PubMed: 40593487
DOI: 10.1038/s41467-025-60543-5

Experimental method

ELECTRON MICROSCOPY (3.7 Å)