5mfw | pdb_00005mfw
Crystal structure of the GluK1 ligand-binding domain in complex with kainate and BPAM-121 at 2.10 A resolution
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 PubMedKainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of AMPA receptors have been reported, no such ligands are available for KARs. In this study, we have investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs. BPAM344 potentiated glutamate-evoked currents of GluK2a 21-fold at the highest concentration tested (200 muM), with an EC50 of 79 muM. BPAM344 markedly decreased desensitization kinetics (from 5.5 to 775 ms), whereas it only had a minor effect on deactivation kinetics. BPAM521 potentiated the recorded peak current amplitude of GluK2a 12-fold at a concentration of 300 muM with an EC50 value of 159 muM, whereas no potentiation of the glutamate-evoked response was observed for BPAM121 at the highest concentration of modulator tested (300 muM). BPAM344 (100 muM) also potentiated the peak current amplitude of KAR subunits GluK3a (59-fold), GluK2a (15-fold), GluK1b (5-fold), as well as the AMPA receptor subunit GluA1i (5-fold). X-ray structures of the three modulators in the GluK1 ligand-binding domain were determined, locating two modulator-binding sites at the GluK1 dimer interface. In conclusion, this study opens for the design of new positive allosteric modulators selective for KARs, which will be of great interest for further investigating the function of KARs in vivo and may prove useful to phamacologically control the activity of neuronal networks. Identification and structure-function study of positive allosteric modulators of kainate receptors.,Larsen AP, Fievre S, Frydenvang K, Francotte P, Pirotte B, Karstrup JS, Mulle C Mol Pharmacol. 2017 Mar 30. pii: mol.116.107599. doi: 10.1124/mol.116.107599. PMID:28360094[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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