Modulation of GluA2–γ5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2

• Published in: Nature structural & molecular biology Vol. 30; no. 10; pp. 1481 - 1494
• Main Authors: Gangwar, Shanti Pal, Yen, Laura Y., Yelshanskaya, Maria V., Korman, Aryeh, Jones, Drew R., Sobolevsky, Alexander I.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2023; Nature Publishing Group
• Subjects: 631/45/269/1149; 631/535/1258/1259; Animals; Anticonvulsants - pharmacology; Antiepileptic agents; Binding; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Channel gating; Desensitization; Electron microscopy; Epilepsy; Humans; Ion channels; Life Sciences; Medical treatment; Membrane Biology; Mental disorders; Mice; Neurological diseases; Neurotransmission; Nitriles; Open channels; Polyamines; Polyamines - pharmacology; Protein Structure; Rats; Receptor mechanisms; Receptors; Receptors, AMPA - chemistry; Receptors, AMPA - metabolism; Spermidine; Structure-function relationships; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/s41594-023-01080-x

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. Gangwar et al. describe the cumulative effect of the potentiating CNIH2 and inhibitory γ5 auxiliary subunits on GluA2 AMPA receptor activation and desensitization gating, polyamine block and noncompetitive inhibition by antiepileptic drug perampanel.