PT - JOURNAL ARTICLE AU - Toshiyuki Ishii AU - Jacob R. Stolz AU - Geoffrey T Swanson TI - Auxiliary proteins are the predominant determinants of differential efficacy of clinical candidates acting as AMPA receptor positive allosteric modulators AID - 10.1124/mol.119.118554 DP - 2020 Jan 01 TA - Molecular Pharmacology PG - mol.119.118554 4099 - http://molpharm.aspetjournals.org/content/early/2020/02/28/mol.119.118554.short 4100 - http://molpharm.aspetjournals.org/content/early/2020/02/28/mol.119.118554.full AB - Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in preclinical and clinical studies. Their therapeutic window is narrow, however, and clinical application will likely only occur if greater discrimination in activity is achieved. Towards that end, we compared the modulatory activity of two PAMs recently considered as clinical candidates, LY451395 (mibampator) and PF-04958242/BIIB104, on recombinant and native AMPA receptors (AMPARs). We found that the principle molecular determinant that shaped modulatory activity of both PAMs on deactivation (recombinant) and decay (synaptic) of AMPARs was the auxiliary protein incorporated into the receptor complexes. AMPARs containing the stargazin/γ2 transmembrane AMPAR regulatory protein (TARP) were slowed to a >10-fold degree by both PAMs as compared to those incorporating γ8 TARP. Neither subunit composition nor flip/flop splice variation had substantive effect. Similarly, stargazin/γ2-containing mossy fiber EPSCs in cerebellar granule neurons were slowed to a ~5-fold greater degree than EPSCs in hippocampal CA1 pyramidal cell neurons, which express the γ8 TARP. LY451395 exhibited greater efficacy than BIIB104 at both synapses. These studies provide insight into the receptor constituents that determine efficacy of sulfonamide PAMs. We conclude that compounds that discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/γ2 efficacy like BIIB104, could act as viable pro-cognitive therapeutics.SIGNIFICANCE STATEMENT Positive allosteric modulators (PAMs) of AMPA receptors enhance cognitive function in a variety of preclinical models. A clearer understanding of the critical determinants of PAM activity could yield critical insight into pathways to maximize their therapeutic index. Here we show that auxiliary proteins for AMPARs play a major but thus-far underappreciated role in shaping recombinant and neuronal AMPAR modulation by two clinical candidates PAMs. These data will inform both clinical outcomes as well as future rational development of new modulators.