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Shisa7 is a GABAA receptor auxiliary subunit controlling benzodiazepine actions

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Science  11 Oct 2019:
Vol. 366, Issue 6462, pp. 246-250
DOI: 10.1126/science.aax5719

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Fine control of brain GABAA receptors

GABAA (γ-aminobutyric acid type A) receptors are ligand-gated anion channels that mediate fast inhibitory transmission in the mammalian brain. Han et al. investigated if a protein called SHISA7 was involved in regulating GABAA receptor expression and function (see the Perspective by Rudolph and Moss). SHISA7 was found at GABA-releasing synapses, where it interacted with GABAA receptors, controlled receptor concentration at the synapse, sped up receptor deactivation kinetics, and modulated some behavioral properties of benzodiazepines. SHISA7 thus affects surface expression, gating kinetics, and pharmacology of GABAA receptors in the brain.

Science, this issue p. 246; see also p. 185

Abstract

The function and pharmacology of γ-aminobutyric acid type A receptors (GABAARs) 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 GABAARs. 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 GABAARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABAAR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.

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