- PDB-8ss2: Structure of AMPA receptor GluA2 complex with auxiliary subunits ... -
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データベース: PDB / ID: 8ss2
タイトル
Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state)
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS083660
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS107253
米国
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)
AR078814
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
CA206573
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2023 タイトル: Modulation of GluA2-γ5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2. 著者: Shanti Pal Gangwar / Laura Y Yen / Maria V Yelshanskaya / Aryeh Korman / Drew R Jones / Alexander I Sobolevsky / 要旨: Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat ...Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment.