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Kainate receptor channel opening and gating mechanism
Shanti Pal Gangwar1, Maria V Yelshanskaya1, Kirill D Nadezhdin1
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
Nature
|May 22, 2024
Summary
Kainate receptors, crucial for brain function and implicated in diseases, were structurally analyzed. Researchers revealed the gating mechanism, offering insights for neurological disorder drug development.
Area of Science:
- Neuroscience
- Structural Biology
- Molecular Pharmacology
Background:
- Kainate receptors are ionotropic glutamate receptors vital for excitatory neurotransmission.
- They play roles in central nervous system development, function, and are linked to neurological/psychiatric disorders.
- Understanding kainate receptor gating is crucial but remains poorly elucidated.
Purpose of the Study:
- To elucidate the molecular mechanism of kainate receptor gating.
- To present high-resolution structures of the GluK2 kainate receptor in the presence of agonists and modulators.
- To provide a structural basis for understanding receptor activation and allosteric modulation.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was employed to determine the structures.
- The GluK2 kainate receptor was studied in complex with glutamate and positive allosteric modulators (concanavalin A and BPAM344).
Main Results:
- Structures reveal how concanavalin A and BPAM344 inhibit desensitization and prolong activation.
- Concanavalin A acts as a spacer, while BPAM344 stabilizes the ligand-binding domain dimer interface.
- Channel opening is characterized by the kinking of all four pore-forming M3 helices.
Conclusions:
- The study reveals the molecular basis of kainate receptor gating.
- Structural insights into agonist binding and allosteric modulation are provided.
- Findings could inform the development of novel therapeutics for neurological disorders targeting kainate receptors.
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