Kainate receptor channel opening and gating mechanism.

Autor: Gangwar SP; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Yelshanskaya MV; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Nadezhdin KD; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Yen LY; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.; Cellular and Molecular Physiology and Biophysics Graduate Program, Columbia University Irving Medical Center, New York, NY, USA., Newton TP; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.; Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University Irving Medical Center, New York, NY, USA., Aktolun M; Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA., Kurnikova MG; Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA., Sobolevsky AI; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. as4005@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jun; Vol. 630 (8017), pp. 762-768. Date of Electronic Publication: 2024 May 22.
DOI: 10.1038/s41586-024-07475-0
Abstrakt: Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission 1-4 . Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism 5-11 . Although structures of kainate receptor domains and subunit assemblies are available 12-18 , the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.
(© 2024. The Author(s).)
Databáze: MEDLINE
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