GluR2 ligand-binding core complexes: importance of the isoxazolol moiety and 5-substituent for the binding mode of AMPA-type agonists.

X-ray structures of the GluR2 ligand-binding core in complex with (S)-Des-Me-AMPA and in the presence and absence of zinc ions have been determined. (S)-Des-Me-AMPA, which is devoid of a substituent in the 5-position of the isoxazolol ring, only has limited interactions with the partly hydrophobic pocket of the ligand-binding site, and adopts an AMPA-like binding mode. The structures, in comparison with other agonist complex structures, disclose the relative importance of the isoxazolol ring and of the substituent in the 5-position for the mode of binding. A relationship appears to exist between the extent of interaction of the ligand with the hydrophobic pocket and the affinity of the ligand.

Localisation and properties of AMPA-insensitive kainate sites: receptor autoradiography and gene expression in rat brain.

Kainic acid (KA)-sensitive glutamate sites have been investigated by receptor autoradiography and in situ hybridisation histochemistry (ISHH) to evaluate their relationship to specific high-affinity KA receptors identified in molecular biological studies. Autoradiography with [3H]KA in the presence of the AMPA-selective antagonist NBQX (1 microM) revealed a widespread distribution of receptors through brain, especially in neocortex, hippocampal CA3, corpus striatum and granule cell layer of cerebellum. Specific binding was insensitive to the AMPA-selective agonist, S-5-fluorowillardiine, but inhibited by kainoids in a manner suggestive of receptor heterogeneity. Expression of the KA-2 receptor subunit mRNA by ISHH was also localised in hippocampal CA3 and cerebellar granule cells, suggesting some high-affinity native KA receptors labelled by [3H]KA were likely to include the KA-2 subunit in their heteromeric assembly.