| 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
The physiological function of kainate receptors (GluK1-GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological evaluation revealed that they are selective for the GluK1 subunit, with 7b being the most subtype-selective ligand reported to date (GluK1 vs GluK3). The antagonist 7a was cocrystallized with the GluK1 ligand binding domain, and an X-ray crystallographic analysis revealed the largest flexibility in GluK1 ligand binding domain opening upon binding of a ligand seen to date. The results provide new insights into the molecular mechanism of GluK1 receptor ligand binding and pave the way to the development of new tool compounds for studying kainate receptor function.
Selective Kainate Receptor (GluK1) Ligands Structurally Based upon 1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: Synthesis, Molecular Modeling, and Pharmacological and Biostructural Characterization.,Venskutonyte R, Butini S, Sanna Coccone S, Gemma S, Brindisi M, Kumar V, Guarino E, Maramai S, Valenti S, Amir A, Valades EA, Frydenvang K, Kastrup JS, Novellino E, Campiani G, Pickering DS J Med Chem. 2011 Jun 13. PMID:21619066[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
- ↑ Venskutonyte R, Butini S, Sanna Coccone S, Gemma S, Brindisi M, Kumar V, Guarino E, Maramai S, Valenti S, Amir A, Valades EA, Frydenvang K, Kastrup JS, Novellino E, Campiani G, Pickering DS. Selective Kainate Receptor (GluK1) Ligands Structurally Based upon 1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: Synthesis, Molecular Modeling, and Pharmacological and Biostructural Characterization. J Med Chem. 2011 Jun 13. PMID:21619066 doi:10.1021/jm2004078
|
