Carrillo Elisa, Montaño Romero Alejandra, Gonzalez Cuauhtemoc U, Turcu Andreea L, Chen Shao-Rui, Chen Hong, Pan Hui-Lin, Vázquez Santiago, Twomey Edward C, Jayaraman Vasanthi
Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
bioRxiv. 2024 Jul 4:2024.07.02.601784. doi: 10.1101/2024.07.02.601784.
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.
美金刚是一种经美国食品药品监督管理局（FDA）批准的药物，可选择性抑制N-甲基-D-天冬氨酸（NMDA）亚型离子型谷氨酸受体（NMDARs），用于治疗痴呆和阿尔茨海默病。NMDARs能使钙离子流入神经元，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，钙离子通透性AMPA亚型离子型谷氨酸受体（AMPARs）会增加钙离子内流。在此，我们证明这些钙离子通透性AMPARs（CP-AMPARs）会被美金刚抑制。电生理学研究表明，美金刚对CP-AMPARs的抑制作用取决于其钙离子通透性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，我们证明美金刚可逆转在一名神经发育障碍患者中发现的功能增强型AMPAR突变，并在神经损伤中抑制CP-AMPARs。我们的研究结果改变了美金刚作用机制的范例，并为靶向CP-AMPARs的治疗方法提供了蓝图。
