Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABA_A receptors

Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by ã-aminobutyric acid type A receptors (GABA_ARs). Although neurosteroids are accepted allosteric modulators of GABA_ARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABA_ARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within á4 subunits, a component of GABA_AR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of á4 subunit-containing GABA_AR subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of á4 subunit-containing GABA_ARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.