iem-1460 and cyclothiazide

The effect of changes in the external concentrations (0.4-10 mM) of Ca2+ ions on AMPA receptors (AMPARs) of different subunit composition was studied on freshly isolated rat brain neurones. Ca2+ produces rapid and reversible voltage-independent inhibition of AMPARs. Ca2+-permeable and Ca2+-impermeable AMPARs are equally sensitive to external Ca2+ suggesting that the effect is not addressed to the ion channel. The inhibition of responses evoked by AMPA is significantly larger than those evoked by kainate or glutamate. Cyclothiazide and aniracetam, which are known to prevent AMPAR desensitization, both greatly diminish inhibition of AMPARs by Ca2+. Cyclothiazide is more potent than aniracetam in both preventing of AMPAR desensitization and protecting against the Ca2+ inhibitory effect on hippocampal pyramidal cells. On giant cholinergic interneurones of striatum, aniracetam but not cyclothiazide significantly prevents inhibition by Ca2+. This agrees with available data on relative abundance of flip and flop splice variants in these cell types. The results suggest that Ca2+ may allosterically increase AMPA receptor desensitization independently on subunit composition and splice variants.

Topics: Adamantane; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Alternative Splicing; Animals; Animals, Newborn; Antihypertensive Agents; Benzothiadiazines; Calcium; Calcium Signaling; Dose-Response Relationship, Drug; Glutamic Acid; Hippocampus; Kainic Acid; Neurons; Nootropic Agents; Pyrrolidinones; Rats; Receptors, AMPA

Subunit composition and abundance of flip version of different AMPA receptor subunits were studied in neurons acutely isolated from hippocampal area CA1 and dentate gyrus. Whole cell recordings were made to record kainate unduced currents. Presence of GluR2 in the receptor complex led to significant decrease of selective channel blocker IEM-1460 potency. Flip versions of AMPA receptor subunits were discriminated on the basis of their sensitivity to cyclothiazide. Principal cell AMPA receptors in both areas were characterized by low sensitivity to IEM-1460 while AMPA receptors of nonprinciple cells exhibited high or intermediate sensitivity to IEM-1460. We observed significantly larger potentiating effect of cyclothiazide on principal cells. Our data indicate that there is a correlation between low sensitivity to IEM-1460 and high sensitivity to cyclothiazide among AMPA receptors of different cells. Principal cells in both regions possess more GluR2 subunits in their AMPA receptor complexes and more abundant flip versions of their subunits in comparison with nonprincipal cells. This correlation is obviously related to functional pecularities of different neurons.

Topics: Adamantane; Alternative Splicing; Animals; Benzothiadiazines; Dentate Gyrus; Excitatory Amino Acid Agonists; Hippocampus; In Vitro Techniques; Interneurons; Kainic Acid; Neurons; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, AMPA