biostudies-literatureAbramian AMNIMH NIH HHSNINDS NIH HHS7132-7https://www.ebi.ac.uk/biostudies/studies/S-EPMC4024867biostudies-literatureUnknown111(19)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 γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within α4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit-containing GABAAR subtypeProceedings of the National Academy of Sciences of the United States of AmericaNeurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors.PMC4024867NS081735R01 NS051195MH097446R01 NS102937T32 NS061764NS056359R01 NS056359R01 NS048045NS051195P01 NS054900R01 NS047478R01 MH118263R01 NS073574R01 MH097446R01 NS081986Maguire JLMoore YEComenencia-Ortiz EAbramian AMModgil AMoss SJNakamura YVien TNTerunuma MDavies PAfalseNeurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA 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 γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within α4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit-containing GABAAR subtype2014-01-01T00:00:00Z2014 May2025-04-05T13:37:36.838Z2019-03-27T01:28:26ZS-EPMC40248672477825910.1073/pnas.1403285111