title: Rapid antidepressants stimulate the decoupling of GABA(B) receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η.
abstract: A single injection of N-methyl-D-aspartate receptor (NMDAR) antagonists produces a rapid antidepressant response. Lasting changes in the synapse structure and composition underlie the effectiveness of these drugs. We recently discovered that rapid antidepressants cause a shift in the γ-aminobutyric acid receptor (GABABR) signaling pathway, such that GABABR activation shifts from opening inwardly rectifiying potassium channels (Kir/GIRK) to increasing resting dendritic calcium signal and mammalian Target of Rapamycin activity. However, little is known about the molecular and biochemical mechanisms that initiate this shift. Herein, we show that GABABR signaling to Kir3 (GIRK) channels decreases with NMDAR blockade. Blocking NMDAR signaling stabilizes the adaptor protein 14-3-3η, which decouples GABABR signaling from Kir3 and is required for the rapid antidepressant efficacy. Consistent with these results, we find that key proteins involved in GABABR signaling bidirectionally change in a depression model and with rapid antidepressants. In socially defeated rodents, a model for depression, GABABR and 14-3-3η levels decrease in the hippocampus. The NMDAR antagonists AP5 and Ro-25-6981, acting as rapid antidepressants, increase GABABR and 14-3-3η expression and decrease Kir3.2. Taken together, these data suggest that the shift in GABABR function requires a loss of GABABR-Kir3 channel activity mediated by 14-3-3η. Our findings support a central role for 14-3-3η in the efficacy of rapid antidepressants and define a critical molecular mechanism for activity-dependent alterations in GABABR signaling.
authors.affiliation: 1] Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX, USA [2] Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Workman
authors.affiliation: Division of Research, Genentech, South San Francisco, CA, USA.
authors.forename: P C G
authors.initials: PC
authors.lastname: Haddick
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bush
authors.affiliation: 1] Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX, USA [2] Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Dilly
authors.affiliation: 1] Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX, USA [2] Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Niere
authors.affiliation: 1] Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX, USA [2] Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
authors.forename: B V
authors.initials: BV
authors.lastname: Zemelman
authors.affiliation: 1] Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX, USA [2] Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA [3] Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Raab-Graham
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D013550:Swimming / Q000523:psychology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014161:Transduction, Genetic; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D048948:14-3-3 Proteins; D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010636:Phenols; D010880:Piperidines; D012333:RNA, Messenger; D018080:Receptors, GABA-B; C109643:Ro 25-6981; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine