Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients
| Autor: | McCarthy, MJ, Wei, H, Landgraf, D, Le Roux, MJ, Welsh, DK |
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| Rok vydání: | 2016 |
| Předmět: |
Kinase
Bipolar Disorder MAP Kinase Signaling System Cells Lithium Medical and Health Sciences Mice Antimanic Agents Dual Specificity Phosphatase 6 Phosphatase Animals Humans Circadian rhythms Phosphorylation Cyclic AMP Response Element-Binding Protein Protein Kinase Inhibitors Reporter Protein Processing ets-Domain Protein Elk-1 Early Growth Response Protein 1 Mitogen-Activated Protein Kinase 1 Psychiatry Cultured Mitogen-Activated Protein Kinase 3 Psychology and Cognitive Sciences Post-Translational Period Circadian Proteins Circadian Rhythm Genes NIH 3T3 Cells RNA Interference |
| Zdroj: | European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, vol 26, iss 8 McCarthy, MJ; Wei, H; Landgraf, D; Le Roux, MJ; & Welsh, DK. (2016). Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients. European Neuropsychopharmacology, 26(8), 1310-1319. doi: 10.1016/j.euroneuro.2016.05.003. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/2rh187qd |
| Popis: | © 2016 Bipolar disorder (BD) is characterized by depression, mania, and circadian rhythm abnormalities. Lithium, a treatment for BD stabilizes mood and increases circadian rhythm amplitude. However, in fibroblasts grown from BD patients, lithium has weak effects on rhythm amplitude compared to healthy controls. To understand the mechanism by which lithium differentially affects rhythm amplitude in BD cells, we investigated the extracellular-signal-regulated kinase (ERK) and related signaling molecules linked to BD and circadian rhythms. In fibroblasts from BD patients, controls and mice, we assessed the contribution of the ERK pathway to lithium-induced circadian rhythm amplification. Protein analyses revealed low phospho-ERK1/2 (p-ERK) content in fibroblasts from BD patients vs. controls. Pharmacological inhibition of ERK1/2 by PD98059 attenuated the rhythm amplification effect of lithium, while inhibition of two related kinases, c-Jun N-terminal kinase (JNK), and P38 did not. Knockdown of the transcription factors CREB and EGR-1, downstream effectors of ERK1/2, reduced baseline rhythm amplitude, but did not alter rhythm amplification by lithium. In contrast, ELK-1 knockdown amplified rhythms, an effect that was not increased further by the addition of lithium, suggesting this transcription factor may regulate the effect of lithium on amplitude. Augmentation of ERK1/2 signaling through DUSP6 knockdown sensitized NIH3T3 cells to rhythm amplification by lithium. In BD fibroblasts, DUSP6 knockdown reversed the BD rhythm phenotype, restoring the ability of lithium to increase amplitude in these cells. We conclude that the inability of lithium to regulate circadian rhythms in BD may reflect reduced ERK activity, and signaling through ELK-1. |
| Databáze: | OpenAIRE |
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