The biophysical and pharmacological properties of AMPARs depend not only on their subunit composition but also on their complement of associated proteins or auxiliary subunits ( Jackson and Nicoll, 2011 Ishii et al., 2020 Coombs and Cull-Candy, 2021 Matthews et al., 2021). For example, the negative allosteric modulator perampanel has proved effective against multiple seizure types ( Tsai et al., 2018 Potschka and Trinka, 2019 Hanada, 2020), but its lack of regional specificity is thought to contribute to side effects that include ataxia and dizziness ( Zwart et al., 2014 Villanueva et al., 2021). This is because, although AMPARs formed from various combinations of the four core subunits (GluA1-4) show differential distribution, the subunits are structurally highly homologous. Although a plethora of AMPAR positive and negative allosteric modulators have been developed ( Partin, 2015 Stenum-Berg et al., 2019 Frydenvang et al., 2021), these lack selectivity for different brain regions. Manipulation of AMPAR activity has been actively pursued as a possible therapy for various neurological and psychiatric disorders, including stroke, depression, pain, epilepsy, and cognitive deficit in Alzheimer’s disease ( Lynch, 2006 Rogawski, 2011 Brogi et al., 2019). Α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are responsible for fast signaling and the expression of plasticity at excitatory synapses throughout the central nervous system (Hansen et al., 2021).
Taken together, our data provide new insight into the mechanism by which γ8-selective drugs inhibit AMPARs.
Additionally, we find that AMPARs incorporating TARP γ2 mutated to contain the JNJ-55511118 binding site, exhibit greater block than seen with AMPARs containing γ8, potentially reflecting differences in TARP stoichiometry. The drug is also effective when applied intracellularly, suggesting it may access its binding site from within the membrane. Moreover, we find that JNJ-55511118 reduces the influence of γ8 on all biophysical measures, aside from its effect on the recovery from desensitization. The drug also modifies hallmark features of AMPAR pharmacology, including the TARP-dependent actions of intracellular polyamines and the partial agonist kainate. Here, using patch-clamp electrophysiological recording from heterologously expressed AMPARs, we show that JNJ-55511118 inhibits peak currents of γ8-containing AMPARs by decreasing their single-channel conductance. However, key details of its mechanism of action are still lacking.
One such inhibitor, JNJ-55511118, has shown considerable promise for the treatment of epilepsy. Recently, several compounds have been identified that selectivity inhibit γ8-containing AMPARs. TARP γ8 has an expression pattern that is distinct from that of other TARPs, being enriched in the hippocampus. The TARPs influence AMPAR biosynthesis and trafficking and enhance receptor responses by slowing desensitization and deactivation and increasing single-channel conductance. The receptors interact with a variety of auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). AMPA-type gultamate receptors (AMPARs) mediate excitatory signaling in the brain and are therapeutic targets for the treatment of diverse neurological disorders.