Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 19, Pages 7132-7137Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1403285111
Keywords
PKC; tonic current; receptor insertion; current rundown
Categories
Funding
- Simons Foundation [206026]
- National Institutes of Health (NIH)-National Institute of Neurological Disorders and Stroke [NS051195, NS056359, NS081735]
- NIH-National Institute of Mental Health [MH097446]
- American Heart Association [09SDG2260557]
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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.-aminobutyric acid type A receptors (GABA(A)Rs). Although neurosteroids are accepted allosteric modulators of GABA(A)Rs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABA(A)Rs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within alpha 4 subunits, a component of GABA(A)R subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of alpha 4 sub-unit-containing GABA(A)R 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 alpha 4 subunit-containing GABA(A)Rs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.
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