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M Kessler, A Arai, A Quan and G Lynch
Center for the Neurobiology of Learning and Memory, University of California, Irvine 92717-3800, USA.
The effects of cyclothiazide on the properties of (R,S)-alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors were studied using equilibrium binding techniques and interactions with other compounds known to modulate the receptors. Cyclothiazide caused a reduction in [3H]AMPA binding in assays carried out in the presence of thiocyanate, a chaotropic ion that markedly increases the affinity of AMPA receptors and accelerates their desensitization. In the absence of thiocyanate, however, cyclothiazide had no reliable effect on the binding of [3H]AMPA or on the affinity for this agonist assessed from the displacement of [3H]CNQX. The interaction of cyclothiazide with the receptor appears not to be changed by the presence of thiocyanate. Analysis of the results with a kinetic model of the AMPA receptor suggests that cyclothiazide does not block receptor desensitization by making the desensitized state inaccessible but rather by stabilizing the active state, i.e., by increasing the affinity of the latter to a point where it becomes energetically more favorable than the desensitized state. GYKI 52466, an atypical benzodiazepine that blocks AMPA receptor-gated currents, did not reverse the changes in binding affinity produced by cyclothiazide in the presence of thiocyanate. Physiological experiments conducted in excised patches collected from hippocampal pyramidal cells indicated that thiocyanate does not block access of GYKI 52466 to AMPA receptors. These results point to the conclusion that cyclothiazide acts at a site on the AMPA receptor different from that for GYKI 52466.
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