Shisa7-Dependent Regulation of GABA A Receptor Single-Channel Gating Kinetics
Year: 2022
Type: article
Abstract: GABA A receptors (GABA A Rs) 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 GABA A R-associated transmembrane proteins. We previously identified Shisa7 as a GABA A R 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 GABA A R 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 GABA A R gating by decreasing the duration and open probability (P o ) within bursts. Kinetic analysis of dwell times, activation modeling, and macroscopic simulations indicate that Shisa7 accelerates GABA A R deactivation by governing the time spent between close and open states during gating. Together, our data provide a mechanistic basis for how Shisa7 controls GABA A R gating kinetics and reveal for the first time that GABA A R single-channel properties can be modulated by an auxiliary subunit. These findings shed light on processes that shape the temporal dynamics of GABAergic transmission.
Source: Journal of Neuroscience
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4304087128