Shisa7-dependent regulation of GABAA receptor single-channel gating kinetics

Abstract

GABAA receptors (GABAARs) mediate the majority of fast inhibitory transmission throughout the brain. Although it is widely known that pore-forming subunits critically determine receptor function, it is unclear whether their single-channel properties are modulated by GABAAR-associated transmembrane proteins. We previously identified Shisa7 as a GABAAR auxiliary subunit that modulates the trafficking, pharmacology, and kinetic properties of these receptors. In particular, Shisa7 accelerates receptor deactivation; however, the underlying mechanisms by which Shisa7 controls GABAAR kinetics have yet to be determined. Here we have performed single-channel recordings and find that while Shisa7 does not change channel slope conductance, it reduces the frequency of openings. Importantly, Shisa7 modulates GABAAR gating by decreasing the duration and open probability (Po) within bursts. Kinetic analysis of dwell times, activation modeling, and macroscopic simulations indicate that Shisa7 accelerates GABAAR deactivation by governing the time spent between close and open states during gating. Together, our data provide a mechanistic basis for how Shisa7 controls GABAAR gating kinetics and reveal for the first time that GABAAR single-channel properties can be modulated by an auxiliary subunit. These findings shed light on processes that shape the temporal dynamics of GABAergic transmission.