GSG1L-containing AMPA receptor complexes are defined by their spatiotemporal expression, native interactome and allosteric sites

Transmembrane AMPA receptor regulatory proteins (TARPs) and germ cell-specific gene 1-like protein (GSG1L) are claudin-type AMPA receptor (AMPAR) auxiliary subunits that profoundly regulate glutamatergic synapse strength and plasticity. While AMPAR-TARP complexes have been extensively studied, less is known about GSG1L-containing AMPARs. Here, we show that GSG1L's spatiotemporal expression, native interactome and allosteric sites are distinct. GSG1L generally expresses late during brain development in a region-specific manner, constituting about 5% of all AMPAR complexes in adulthood. While GSG1L can co-assemble with TARPs or cornichons (CNIHs), it also assembles as the sole auxiliary subunit. Unexpectedly, GSG1L acts through two discrete evolutionarily-conserved sites on the agonist-binding domain with a weak allosteric interaction at the TARP/KGK site to slow desensitization, and a stronger interaction at a different site that slows recovery from desensitization. Together, these distinctions help explain GSG1L's evolutionary past and how it fulfills a unique signaling role within glutamatergic synapses. TARPs and GSG1L are evolutionarily- and structurally-related AMPA receptor auxiliary subunits that differ in function through unresolved mechanisms. Here, the authors provide insight into the spatiotemporal expression, composition, and functionality of GSG1L-containing protein complexes.

Automated summary

This study reveals the unique characteristics of GSG1L in terms of its spatiotemporal expression, composition, and functionality. It is expressed late during brain development in a region-specific manner and constitutes about 5% of all AMPAR complexes in adulthood. GSG1L can assemble with TARPs or CNIHs, but it also has the ability to function as the sole auxiliary subunit. Through its interaction with two evolutionarily conserved sites on the agonist-binding domain, GSG1L weakly slows desensitization at the TARP/KGK site and strongly slows recovery from desensitization at a different site. These findings provide insights into the unique signaling role of GSG1L within glutamatergic synapses.