Kainate receptor channel opening and gating mechanism

Shanti Pal Gangwar, Maria V. Yelshanskaya, Kirill D. Nadezhdin, Laura Y. Yen, Thomas P. Newton, Muhammed Aktolun, Maria G. Kurnikova and Alexander I. Sobolevsky ()
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Shanti Pal Gangwar: Columbia University
Maria V. Yelshanskaya: Columbia University
Kirill D. Nadezhdin: Columbia University
Laura Y. Yen: Columbia University
Thomas P. Newton: Columbia University
Muhammed Aktolun: Carnegie Mellon University
Maria G. Kurnikova: Carnegie Mellon University
Alexander I. Sobolevsky: Columbia University

Nature, 2024, vol. 630, issue 8017, 762-768

Abstract: Abstract Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission1–4. 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 autism5–11. Although structures of kainate receptor domains and subunit assemblies are available12–18, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07475-0

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