title: Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients.
abstract: 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.
  
  
  
  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.
authors.affiliation: Research and Psychiatry Service, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Dr, MC 116A, San Diego, CA 92161, USA; Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, USA. Electronic address: mmccarthy@ucsd.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCarthy
authors.affiliation: Research and Psychiatry Service, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Dr, MC 116A, San Diego, CA 92161, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, USA.
authors.forename: Dominic
authors.initials: D
authors.lastname: Landgraf
authors.affiliation: Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Le Roux
authors.affiliation: Research and Psychiatry Service, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Dr, MC 116A, San Diego, CA 92161, USA; Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Welsh
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054642:Dual Specificity Phosphatase 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D050807:ets-Domain Protein Elk-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018692:Antimanic Agents; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C497325:EGR1 protein, human; C494112:ELK1 protein, human; D051766:Early Growth Response Protein 1; C421902:PER2 protein, human; D056950:Period Circadian Proteins; D047428:Protein Kinase Inhibitors; D050807:ets-Domain Protein Elk-1; D008094:Lithium; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6
keywords: Bipolar disorder; Circadian rhythms; Kinase; Lithium; Phosphatase