Ca2+-dependent desensitization of AMPA receptors

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