美金刚抑制钙通透性AMPA受体。

Memantine inhibits calcium-permeable AMPA receptors.

作者信息

Carrillo Elisa, Montaño Romero Alejandra, Gonzalez Cuauhtemoc U, Turcu Andreea L, Vázquez Santiago, Twomey Edward C, Jayaraman Vasanthi

机构信息

Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX, USA.

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

出版信息

Nat Commun. 2025 Jul 1;16(1):5576. doi: 10.1038/s41467-025-60543-5.

DOI:10.1038/s41467-025-60543-5

PMID:40593487

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.

摘要

美金刚是一种经美国食品药品监督管理局（FDA）批准的药物，被认为可选择性抑制离子型谷氨酸受体（NMDARs）的NMDA亚型。NMDARs能使钙流入神经元，对正常脑功能至关重要。然而，越来越多的证据表明，在神经疾病中，钙通过可通透钙的离子型谷氨酸受体（AMPARs）的AMPA亚型流入会增加。在此，我们证明这些可通透钙的AMPARs（CP-AMPARs）会被美金刚抑制。电生理学揭示，美金刚对CP-AMPARs的抑制作用取决于它们的钙通透性以及其神经元辅助亚基跨膜AMPAR调节蛋白（TARPs）的存在。通过冷冻电子显微镜，我们阐明美金刚以一种不同于NMDARs的独特作用机制阻断CP-AMPAR离子通道。此外，我们证明美金刚可抑制在一名神经发育障碍患者中发现的功能增强型AMPAR突变。我们的研究结果为利用该位点设计更具针对性的靶向CP-AMPARs的药物开辟了潜在途径。