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Publication Abstract from PubMed

Synaptic complexes of alpha-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 gamma5 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 gamma5, 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.

Modulation of GluA2-gamma5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2.,Gangwar SP, Yen LY, Yelshanskaya MV, Korman A, Jones DR, Sobolevsky AI Nat Struct Mol Biol. 2023 Oct;30(10):1481-1494. doi: 10.1038/s41594-023-01080-x. , Epub 2023 Aug 31. PMID:37653241^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.