1. Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients.
- Author
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McCarthy MJ, Wei H, Landgraf D, Le Roux MJ, and Welsh DK
- Subjects
- Animals, Antimanic Agents therapeutic use, Bipolar Disorder drug therapy, Bipolar Disorder pathology, Cells, Cultured, Cyclic AMP Response Element-Binding Protein antagonists & inhibitors, Cyclic AMP Response Element-Binding Protein genetics, Cyclic AMP Response Element-Binding Protein metabolism, Dual Specificity Phosphatase 6 antagonists & inhibitors, Dual Specificity Phosphatase 6 genetics, Dual Specificity Phosphatase 6 metabolism, Early Growth Response Protein 1 antagonists & inhibitors, Early Growth Response Protein 1 genetics, Early Growth Response Protein 1 metabolism, Genes, Reporter drug effects, Humans, Lithium therapeutic use, MAP Kinase Signaling System drug effects, Mice, Mitogen-Activated Protein Kinase 1 antagonists & inhibitors, Mitogen-Activated Protein Kinase 1 chemistry, Mitogen-Activated Protein Kinase 3 antagonists & inhibitors, Mitogen-Activated Protein Kinase 3 chemistry, NIH 3T3 Cells, Period Circadian Proteins agonists, Period Circadian Proteins genetics, Period Circadian Proteins metabolism, Phosphorylation drug effects, Protein Kinase Inhibitors pharmacology, Protein Processing, Post-Translational drug effects, RNA Interference, ets-Domain Protein Elk-1 antagonists & inhibitors, ets-Domain Protein Elk-1 genetics, Antimanic Agents pharmacology, Bipolar Disorder metabolism, Circadian Rhythm drug effects, Lithium pharmacology, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, ets-Domain Protein Elk-1 metabolism
- Abstract
Unlabelled: 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., (Published by Elsevier B.V.)
- Published
- 2016
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