Abstract

Glutamate is the major excitatory neurotransmitter in brain, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) mediate the majority of postsynaptic depolarization. AMPAR ion channels display rapid gating, and their deactivation and desensitization determine the timing of synaptic transmission. AMPAR potentiators slow channel deactivation and desensitization, and these compounds represent exciting therapies for mental and neurodegenerative diseases. Previous studies showed that the AMPAR potentiators cyclothiazide and 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide display a preference for flip and flop alternatively spliced versions of glutamate receptor subunits, respectively. Here, we find that the AMPAR auxiliary subunit stargazin changes this pharmacology and makes both spliced forms of glutamate receptor subunit 1 sensitive to both classes of potentiator. Stargazin also enhances the effect of AMPAR potentiators on channel deactivation. This work demonstrates that stargazin controls AMPAR potentiator pharmacology, which has important implications for development of AMPAR potentiators as therapeutic agents.