Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors

Armen M. Abramian, Eydith Comenencia-Ortiz, Amit Modgil, Thuy N. Vien, Yasuko Nakamura, Yvonne E. Moore, Jamie L. Maguire, Miho Terunuma, Paul A. Davies*, Stephen J. Moss

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


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 (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 á4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of á4 subunit-containing GABAAR 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 GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.

Original languageEnglish (US)
Pages (from-to)7132-7137
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - May 13 2014
Externally publishedYes


  • Current rundown
  • PKC
  • Receptor insertion
  • Tonic current

ASJC Scopus subject areas

  • General


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