Shisa7 is a GABA _A receptor auxiliary subunit controlling benzodiazepine actions

Abstract

The function and pharmacology of γ-aminobutyric acid type A receptors (GABA_ARs) are of great physiological and clinical importance and have long been thought to be determined by the channel pore-forming subunits. We discovered that Shisa7, a single-passing transmembrane protein, localizes at GABAergic inhibitory synapses and interacts with GABA_ARs. Shisa7 controls receptor abundance at synapses and speeds up the channel deactivation kinetics. Shisa7 also potently enhances the action of diazepam, a classic benzodiazepine, on GABA_ARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABA_AR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.