Cyclothiazide potentiates agonist responses at human AMPA/kainate receptors expressed in oocytes

2,3‐Benzodiazepines (GYKI 52466 and Analogs): Negative Allosteric Modulators of AMPA Receptors

“…This fact, together with the reversibility of their effects in vivo, suggests that they bind to an allosteric site. This idea is further confirmed by the observations that GYKI compounds also exert an effect on recombinant receptors (90,160,199), and that binding of GYKI compounds to CNS membrane preparations could not be displaced by non-NMDA receptor agonists (176). This allosteric binding site is probably not in the pore region of the receptor, since the block of currents by GYKI compounds did not require opening of the channels (42,129) and showed no (42), or weak (129,205) voltage dependence.…”

“…The above mentioned observation that both cyclothiazide and GYKI 53655 also act on nicotinic receptors (123, and that they influence desensitization, in a similar way to non-NMDA receptors, raises the possibility that the binding site is on a separate modulatory protein that can associate to different ligand gated ion channels. The results of expression studies seem to dispute the hypothesis, however: both cyclothiazide and GYKI 52466 have an effect on the currents mediated by recombinant GluRs (90,134,160,199). Even the location of the positive allosteric modulatory site on the AMPAkainate receptor could be questioned; the critical residues may be in the alternatively spliced (flip/flop) region (134).…”

Divalent Cation Entry in Cultured Rat Cerebellar Granule Cells Measured Using Mn2+ Quench of Fura 2 Fluorescence

“…1993), and Na+ entry via these channels would be likely to depolarize cells and activate VOCCs (Reichling and MacDermott, 1993). AMPA caused only very small [Ca2+Ii elevations in cerebellar granule cells, a finding which may be due partly to receptor desensitization (Sharp et al, 1994). It is therefore to be expected that any divalent cationpermeant channel activation evoked by AMPA would be small, and so might not be detected by the Mn2+ quench method, making it difficult to distinguish between Ca2+ entry and release from stores as the cause of this response.…”

Allosteric interactions between cyclothiazide and AMPA/kainate receptor antagonists

“…Huettner and Wilding (1995) reported comparable IC50 differences for GYKI between cortical AMPA receptors and DRG kainate receptors. Moreover, Lerma and colleagues (Paternain et al, 1995) (Partin et al, 1994 (Sharp et al, 1994). Because cyclothiazide acts upon homomeric channels composed of any one of the GluRA-Dflip subunits, its site of action must be an intrinsic element of the individual AMPA receptor subunit.…”