Abstract
Memantine is an US Food and Drug Administration (FDA) approved drug that selectively inhibits NMDA-subtype ionotropic glutamate receptors (NMDARs) for treatment of dementia and Alzheimer’s. 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 reverses a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder and inhibits CP-AMPARs in nerve injury. Our findings alter the paradigm for the memantine mechanism of action and provide a blueprint for therapeutic approaches targeting CP-AMPARs.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Lead Contact: Vasanthi Jayaraman, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, MSB 6.532, 6431 Fannin St, Houston, TX 77030 Tel.: (713) 500-6236, Fax: (713) 500-0652, email: vasanthi.jayaraman{at}uth.tmc.edu
Data Availability
Cryo-EM maps and structural coordinates will be deposited into the electron microscopy data bank (EMDB) and protein data bank (pdb), respectively, upon publication.