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Stargazin, an AMPA receptor auxiliary subunit, increases AMPA receptor surface expression and ampakine binding affinity, drastically modulating ampakine gating kinetics and pharmacological properties.It was previously reported that Stargazin (STG) enhances the surface expression of AMPA receptors, controls receptor gating and slows channel desensitization as an auxiliary subunit of the receptors. Ampakines are a class of AMPA receptor positive allosteric modulators that modify rates of transmitter binding, channel activity and desensitization parameters. As such, they have shown efficacy in animal models of neurodegenerative diseases, where excitatory synaptic transmission is compromised. Given the functional similarities between STG and ampakines, the current study sought to probe interactions between STG and ampakine gating properties. The effects of the high impact ampakines, CX614 and cyclothiazide (CTZ), were compared with homomeric GluR1-flip (Glur1i) and GluR2-flop (Glur2o) receptors expressed in HEK293 cells by transient transfection with or without STG gene. STG dramatically enhanced the surface expression of AMPA receptors and increased glutamate-induced steady-state currents during desensitization. STG also increased ratios of 500 μM kainate and 500 μM glutamate activated steady-state currents. STG reduced association rates of ampakines and differentially affected the dissociation rates for both CX614 and CTZ on desensitized receptors. The estimated Kd value for CX614 was lowered from 340 μM to 70 μM, whereas that for CTZ was lowered from 170 μM to 6 μM by STG. The data suggest that Stargazin can dramatically alter the conformation of the receptor dimer interface where CX614 and CTZ are known to bind. This work also demonstrates the importance of considering STG interactions when developing ampakines to treat neurodegenerative diseases in which AMPAergic signaling is compromised.