Neurosteroids 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 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 α4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Armen M
AM
Abramian
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Eydith
E
Comenencia-Ortiz
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Amit
A
Modgil
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Thuy N
TN
Vien
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Yasuko
Y
Nakamura
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; andDepartment of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6B, United Kingdom.
Yvonne E
YE
Moore
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Jamie L
JL
Maguire
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Miho
M
Terunuma
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and stephen.moss@tufts.edu paul.davies@tufts.edu.
Paul A
PA
Davies
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; andDepartment of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6B, United Kingdom stephen.moss@tufts.edu paul.davies@tufts.edu.
Stephen J
SJ
Moss
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
C546260:GABRA4 protein, human; D018377:Neurotransmitter Agents; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D011493:Protein Kinase C
PKC; current rundown; receptor insertion; tonic current