Structural highlights
Function
GRIK2_RAT Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus. Modulates cell surface expression of NETO2 (By similarity).[1] [2]
Publication Abstract from PubMed
Kainate receptors belong to the family of ionotropic glutamate receptors and contribute to the majority of fast excitatory neurotransmission. Consequently, they also play a role in brain diseases. Therefore, understanding how these receptors can be modulated is of importance. Our study provides a crystal structure of the dimeric ligand-binding domain of the kainate receptor GluK2 in complex with L-glutamate and the small-molecule positive allosteric modulator, BPAM344, in an active-like conformation. The role of Thr535 and Gln786 in modulating GluK2 by BPAM344 was investigated using a calcium-sensitive fluorescence-based assay on transiently transfected cells expressing GluK2 and mutants hereof. This study may aid in the design of compounds targeting kainate receptors, expanding their potential as targets for the treatment of brain diseases.
The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2.,Bay Y, Egeberg Jeppesen M, Frydenvang K, Francotte P, Pirotte B, Pickering DS, Kristensen AS, Kastrup JS FEBS Lett. 2024 Apr;598(7):743-757. doi: 10.1002/1873-3468.14824. Epub 2024 Feb , 18. PMID:38369668[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Martin S, Nishimune A, Mellor JR, Henley JM. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature. 2007 May 17;447(7142):321-5. Epub 2007 May 7. PMID:17486098 doi:nature05736
- ↑ Weston MC, Schuck P, Ghosal A, Rosenmund C, Mayer ML. Conformational restriction blocks glutamate receptor desensitization. Nat Struct Mol Biol. 2006 Dec;13(12):1120-7. Epub 2006 Nov 19. PMID:17115050 doi:http://dx.doi.org/10.1038/nsmb1178
- ↑ Bay Y, Egeberg Jeppesen M, Frydenvang K, Francotte P, Pirotte B, Pickering DS, Kristensen AS, Kastrup JS. The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2. FEBS Lett. 2024 Apr;598(7):743-757. PMID:38369668 doi:10.1002/1873-3468.14824
