Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Image credit: Dave Cutler (artist).
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Abstract
Lithium, one of the most effective drugs for the treatment of bipolar (manic-depressive) disorder, also has dramatic effects on morphogenesis in the early development of numerous organisms. How lithium exerts these diverse effects is unclear, but the favored hypothesis is that lithium acts through inhibition of inositol monophosphatase (IMPase). We show here that complete inhibition of IMPase has no effect on the morphogenesis of Xenopus embryos and present a different hypothesis to explain the broad action of lithium. Our results suggest that lithium acts through inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), which regulates cell fate determination in diverse organisms including Dictyostelium, Drosophila, and Xenopus. Lithium potently inhibits GSK-3 beta activity (Ki = 2 mM), but is not a general inhibitor of other protein kinases. In support of this hypothesis, lithium treatment phenocopies loss of GSK-3 beta function in Xenopus and Dictyostelium. These observations help explain the effect of lithium on cell-fate determination and could provide insights into the pathogenesis and treatment of bipolar disorder.
A molecular mechanism for the effect of lithium on development
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Several large or long-lived animals seem strangely resistant to developing cancer. Elucidating the reasons why could lead to promising cancer-fighting strategies in humans.
Image credit: Shutterstock.com/ronnybas frimages.
PNAS Profile of NAS member and biochemist Hao Wu
A study suggests a putative gene-expression hallmark common to monogamous male vertebrates of some species, namely cichlid fishes, dendrobatid frogs, passeroid songbirds, common voles, and deer mice, and identifies 24 candidate genes potentially associated with monogamy.
Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Physical and social well-being in old age are linked to self-assessments of life worth, and a spectrum of behavioral, economic, health, and social variables may influence whether aging individuals believe they are leading meaningful lives.
Image courtesy of Pixabay/MabelAmber.
More Articles of This Classification
Related Content
Cited by...
- Wnt5a induces and maintains prostate cancer cells dormancy in bone
- Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis
- Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells
- Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy
- WNT Signaling in Cardiac and Vascular Disease
- Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene
- Down-regulation of the Wnt/{beta}-catenin signaling pathway by Cacnb4
- Nuclear {alpha}-catenin mediates the DNA damage response via {beta}-catenin and nuclear actin
- Spemann organizer transcriptome induction by early beta-catenin, Wnt, Nodal, and Siamois signals in Xenopus laevis
- Effect of lithium on ventricular remodelling in infarcted rats via the Akt/mTOR signalling pathways
- Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization
- Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis
- Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in the Drosophila Voltage-Gated Sodium Channel Gene paralytic
- A Novel Glycogen Synthase Kinase-3 Inhibitor Optimized for Acute Myeloid Leukemia Differentiation Activity
- Long-Term Lithium Use and Risk of Renal and Upper Urinary Tract Cancers
- Reck enables cerebrovascular development by promoting canonical Wnt signaling
- Stringent Control of NFE2L3 (Nuclear Factor, Erythroid 2-Like 3; NRF3) Protein Degradation by FBW7 (F-box/WD Repeat-containing Protein 7) and Glycogen Synthase Kinase 3 (GSK3)
- FXR1P is a GSK3{beta} substrate regulating mood and emotion processing
- Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study
- Glycogen synthase kinase-3 (Gsk-3) plays a fundamental role in maintaining DNA methylation at imprinted loci in mouse embryonic stem cells
- MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance
- Protection against Klebsiella pneumoniae Using Lithium Chloride in an Intragastric Infection Model
- Hepatic Proteome Analysis of Atlantic Salmon (Salmo salar) After Exposure to Environmental Concentrations of Human Pharmaceuticals
- Downregulated miR329 and miR410 Promote the Proliferation and Invasion of Oral Squamous Cell Carcinoma by Targeting Wnt-7b
- Phosphorylation of the cytoskeletal protein CAP1 controls its association with cofilin and actin
- MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway
- PI4KII{alpha} phosphorylation by GSK3 directs vesicular trafficking to lysosomes
- Receptor heterodimerization as a novel mechanism for the regulation of Wnt/{beta}-catenin signaling
- Nkx2-5 regulates cardiac growth through modulation of Wnt signaling by R-spondin3
- DOCK5 functions as a key signaling adaptor that links Fc{varepsilon}RI signals to microtubule dynamics during mast cell degranulation
- Novel Neuroprotective GSK-3{beta} Inhibitor Restricts Tat-Mediated HIV-1 Replication
- Lithium induces microcysts and polyuria in adolescent rat kidney independent of cyclooxygenase-2
- Paracrine activation of WNT/{beta}-catenin pathway in uterine leiomyoma stem cells promotes tumor growth
- Lithium Attenuates IFN-{beta} Production and Antiviral Response via Inhibition of TANK-Binding Kinase 1 Kinase Activity
- Regulation of Th1 Cells and Experimental Autoimmune Encephalomyelitis by Glycogen Synthase Kinase-3
- Anteroposterior and dorsoventral patterning are coordinated by an identical patterning clock
- Pharmacokinetics, Metabolism, and Excretion of the Glycogen Synthase Kinase-3 Inhibitor LY2090314 in Rats, Dogs, and Humans: A Case Study in Rapid Clearance by Extensive Metabolism with Low Circulating Metabolite Exposure
- Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder
- Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer
- Wnt Signaling in Vertebrate Axis Specification
- Deletion of GSK3{beta} in D2R-expressing neurons reveals distinct roles for {beta}-arrestin signaling in antipsychotic and lithium action
- A dual function for canonical Wnt/{beta}-catenin signaling in the developing mammalian cochlea
- Targeting Wnt Pathways in Disease
- Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model
- Wnt Proteins
- A zebrafish Notum homolog specifically blocks the Wnt/{beta}-catenin signaling pathway
- 3'-5' Phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo
- Roles of Heparan Sulfate Sulfation in Dentinogenesis
- Lithium enhances remyelination of peripheral nerves
- Interactions Between {beta}-Catenin and Transforming Growth Factor-{beta} Signaling Pathways Mediate Epithelial-Mesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)
- Adenomatous Polyposis Coli (APC) Regulates Multiple Signaling Pathways by Enhancing Glycogen Synthase Kinase-3 (GSK-3) Activity
- Wnt Signaling in the Vertebrate Central Nervous System: From Axon Guidance to Synaptic Function
- Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia
- Collapsin Response Mediator Proteins (CRMPs) Are a New Class of Microtubule-associated Protein (MAP) That Selectively Interacts with Assembled Microtubules via a Taxol-sensitive Binding Interaction
- Modulation of canonical Wnt signaling by the extracellular matrix component biglycan
- Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development
- Bioinformatic Prediction and Confirmation of {beta}-Adducin as a Novel Substrate of Glycogen Synthase Kinase 3
- Wnt5a is a cell-extrinsic factor that supports self-renewal of mouse spermatogonial stem cells
- Galangin Suppresses the Proliferation of {beta}-Catenin Response Transcription-Positive Cancer Cells by Promoting Adenomatous Polyposis Coli/Axin/Glycogen Synthase Kinase-3{beta}-Independent {beta}-Catenin Degradation
- AMP-activated Protein Kinase (AMPK) Activation and Glycogen Synthase Kinase-3{beta} (GSK-3{beta}) Inhibition Induce Ca2+-independent Deposition of Tight Junction Components at the Plasma Membrane
- Inhibition of TGFBIp Expression by Lithium: Implications for TGFBI-Linked Corneal Dystrophy Therapy
- FGF/MAPK/Ets signaling renders pigment cell precursors competent to respond to Wnt signal by directly controlling Ci-Tcf transcription
- Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development
- Epithelial cell proliferation in the developing zebrafish intestine is regulated by the Wnt pathway and microbial signaling via Myd88
- Glycogen Synthase Kinase-3 Is an Early Determinant in the Differentiation of Pathogenic Th17 Cells
- Novel Synthetic Antagonists of Canonical Wnt Signaling Inhibit Colorectal Cancer Cell Growth
- Protein tyrosine kinase 7 has a conserved role in Wnt/{beta}-catenin canonical signalling
- Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci
- N-Glycosylation Gene DPAGT1 Is a Target of the Wnt/{beta}-Catenin Signaling Pathway
- WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification
- Ectopic Mitf in the Embryonic Chick Retina by Co-transfection of {beta}-Catenin and Otx2
- Kctd15 inhibits neural crest formation by attenuating Wnt/{beta}-catenin signaling output
- The Postsynaptic Adenomatous Polyposis Coli (APC) Multiprotein Complex Is Required for Localizing Neuroligin and Neurexin to Neuronal Nicotinic Synapses in Vivo
- Pharmacological and Genetic Reversal of Age-Dependent Cognitive Deficits Attributable to Decreased presenilin Function
- Identification and regulation of glycogen synthase kinase-3 during bovine embryo development
- Protein Phosphatase 2A and Glycogen Synthase Kinase 3 Signaling Modulate Prepulse Inhibition of the Acoustic Startle Response by Altering Cortical M-Type Potassium Channel Activity
- A kinesin signaling complex mediates the ability of GSK-3{beta} to affect mood-associated behaviors
- Coincidence Detection and Stress Modulation of Spike Time-Dependent Long-Term Depression in the Hippocampus
- Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells
- Triptolide Inhibits IL-12/IL-23 Expression in APCs via CCAAT/Enhancer-Binding Protein {alpha}
- GSK3{beta} Mediates Renal Response to Vasopressin by Modulating Adenylate Cyclase Activity
- Prostaglandin Promotion of Osteocyte Gap Junction Function through Transcriptional Regulation of Connexin 43 by Glycogen Synthase Kinase 3/{beta}-Catenin Signaling
- Regulation of Serotonin 1B Receptor by Glycogen Synthase Kinase-3
- A BMP-Shh negative-feedback loop restricts Shh expression during limb development
- Knockout mice in understanding the mechanism of action of lithium
- Employing multiple models, methods and mechanisms in bipolar disorder research
- Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder?
- Validating GSK3 as an in vivo target of lithium action
- Cellular consequences of inositol depletion
- Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies
- Elevated levels of IL-1{beta} in Fanconi anaemia group A patients due to a constitutively active phosphoinositide 3-kinase-Akt pathway are capable of promoting tumour cell proliferation