Structural highlights
Function
GRIK1_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.[1]
Publication Abstract from PubMed
Kainate receptors play an important role in the central nervous system by mediating postsynaptic excitatory neurotransmission and modulating the release of the inhibitory neurotransmitter GABA through a presynaptic mechanism. To date, only three structures of the ligand-binding domain (LBD) of the kainate receptor subunit GluK1 in complex with positive allosteric modulators have been determined by X-ray crystallography, all belonging to class II modulators. Here, we report a high-resolution structure of GluK1-LBD in complex with kainate and BPAM538, which belongs to the full-spanning class III. One BPAM538 molecule binds at the GluK1 dimer interface, thereby occupying two allosteric binding sites simultaneously. BPAM538 stabilizes the active receptor conformation with only minor conformational changes being introduced to the receptor. Using a calcium-sensitive fluorescence-based assay, a 5-fold potentiation of the kainate response (100â¯muM) was observed in presence of 100â¯muM BPAM538 at GluK1(Q)(b), whereas no potentiation was observed at GluK2(VCQ)(a). Using electrophysiology recordings of outside-out patches excised from HEK293 cells, BPAM538 increased the peak response of GluK1(Q)(b) co-expressed with NETO2 to rapid application of 10â¯mM L-glutamate with 130â¯+/-â¯20â¯%, and decreased desensitization determined as the steady-state/peak response ratio from 23â¯+/-â¯2â¯% to 90â¯+/-â¯4â¯%. Based on dose-response relationship experiments on GluK1(Q)(b) the EC(50) of BPAM538 was estimated to be 57.5â¯+/-â¯29.2â¯muM.
Crystal structure of the GluK1 ligand-binding domain with kainate and the full-spanning positive allosteric modulator BPAM538.,Bay Y, Cabello FJM, Koens CC, Frantsen SM, Pickering DS, Frydenvang K, Francotte P, Pirotte B, Kristensen AS, Bowie D, Kastrup JS J Struct Biol. 2024 Jul 28:108113. doi: 10.1016/j.jsb.2024.108113. PMID:39079583[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mayer ML, Ghosal A, Dolman NP, Jane DE. Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci. 2006 Mar 15;26(11):2852-61. PMID:16540562 doi:26/11/2852
- ↑ Bay Y, Cabello FJM, Koens CC, Frantsen SM, Pickering DS, Frydenvang K, Francotte P, Pirotte B, Kristensen AS, Bowie D, Kastrup JS. Crystal structure of the GluK1 ligand-binding domain with kainate and the full-spanning positive allosteric modulator BPAM538. J Struct Biol. 2024 Jul 28:108113. PMID:39079583 doi:10.1016/j.jsb.2024.108113
