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- W2066406363 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." @default.
- W2066406363 created "2016-06-24" @default.
- W2066406363 creator A5005558102 @default.
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- W2066406363 creator A5082864455 @default.
- W2066406363 creator A5086527034 @default.
- W2066406363 date "2015-01-06" @default.
- W2066406363 modified "2023-10-17" @default.
- W2066406363 title "Rapid antidepressants stimulate the decoupling of GABAB receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η" @default.
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- W2066406363 doi "https://doi.org/10.1038/mp.2014.165" @default.
- W2066406363 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4357863" @default.
- W2066406363 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25560757" @default.
- W2066406363 hasPublicationYear "2015" @default.