Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94

Background Valproate is a standard treatment for bipolar disorder and a first-line mood stabilizer. The molecular mechanisms underlying its actions in bipolar disorder are unclear. It has been suggested that the action of valproate is linked to changes in gene expression and induction of endoplasmic reticulum (ER) stress-response proteins. Principal Findings Here we show that valproate modulates the ER stress response through the regulation of WFS1, an important component for mitigating ER stress. Therapeutic concentrations of valproate induce expression of WFS1 mRNA and activate the WFS1 promoter. In addition, WFS1 forms a complex with GRP94, an ER stress-response protein, in which valproate dose-dependently enhances its dissociation from GRP94. Conclusions These results suggest that the therapeutic effects of valproate in bipolar disorder may be mediated by WFS1 expression and its dissociation from GRP94.

• Publication year

  2009

• Venue

  PLoS ONE

• Publication date

  2009-01-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0004134PMID 19125190PMCID 2607540
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• OS-9 and GRP94 deliver mutant α1-antitrypsin to the Hrd1–SEL1L ubiquitin ligase complex for ERAD

  2008cited by this paper
• The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?

  2007cited by this paper
• Association analysis of HSP90B1 with bipolar disorder

  2007cited by this paper
• Molecular genetics of bipolar disorder and depression

  2007cited by this paper
• Signal integration in the endoplasmic reticulum unfolded protein response

  2007cited by this paper
• That which does not kill me makes me stronger: adapting to chronic ER stress.

  2007cited by this paper
• XBP1 induces WFS1 through an endoplasmic reticulum stress response element‐like motif in SH‐SY5Y cells

  2006cited by this paper
• Valproate: past, present, and future.

  2006cited by this paper
• WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic β-Cells*

  2005cited by this paper
• Wolframin mutations and hospitalization for psychiatric illness

  2005cited by this paper
• Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen*

  2001cited by this paper
• Increased expression of endoplasmic reticulum stress proteins following chronic valproate treatment of rat C6 glioma cells.

  2000cited by this paper
• Mechanisms of action of valproate: a commentatory.

  2000cited by this paper
• Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1.

  1999cited by this paper
• Valproate robustly enhances AP-1 mediated gene expression.

  1999cited by this paper
• Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein.

  1998cited by this paper
• Geldanamycin, an hsp90/GRP94‐binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway

  1998cited by this paper
• A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome)

  1998cited by this paper
• Identification of the cis-Acting Endoplasmic Reticulum Stress Response Element Responsible for Transcriptional Induction of Mammalian Glucose-regulated Proteins

  1998cited by this paper
• Predisposition of Wolfram syndrome heterozygotes to psychiatric illness

  1998cited by this paper
• Increase in AP-1 Transcription Factor DNA Binding Activity by Valproic Acid

  1997cited by this paper
• Psychiatric findings in Wolfram syndrome homozygotes.

  1990cited by this paper
• The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins

  1988cited by this paper
• MANIC DEPRESSIVE ILLNESS

  1970cited by this paper

• Reciprocal rescue of Wolfram syndrome by two causative genes

  2025cites this paper
• Could R‐Ketamine and Wolfram Syndrome Inform Understanding of Depression and Suicidality? A Sigma‐1 Receptor‐Based Perspective

  2025cites this paper
• ISR inhibition reverses pancreatic β-cell failure in Wolfram syndrome models

  2024cites this paper
• Cardiac Wolframinopathies: A Case Report of Myocarditis and a Literature Review of Cardiac Involvement in Wolfram Syndrome 1

  2024cites this paper
• Novel WFS1 variants are associated with different diabetes phenotypes

  2024cites this paper
• New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview

  2024cites this paper
• Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder

  2023cites this paper
• Mitochondria dysfunction and bipolar disorder: From pathology to therapy

  2023cites this paper
• Chronic Stress Alters Hippocampal Renin-Angiotensin-Aldosterone System Component Expression in an Aged Rat Model of Wolfram Syndrome

  2023cites this paper
• A Pair of Siblings With Wolfram Syndrome: A Review of the Literature and Treatment Options

  2023cites this paper
• Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis

  2022cites this paper
• The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome

  2022cites this paper
• Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders

  2022cites this paper
• Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome

  2022cites this paper
• Maternal stress induced endoplasmic reticulum stress and impaired pancreatic islets’ insulin secretion via glucocorticoid receptor upregulation in adult male rat offspring

  2022cites this paper
• Diabetes Out-of-the-Box: Diabetes Mellitus and Impairment in Hearing and Vision

  2022cites this paper
• Wolfram Syndrome 1: From Genetics to Therapy

  2022cites this paper
• Collaboration for rare diabetes: understanding new treatment options for Wolfram syndrome

  2021cites this paper
• Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders

  2021cites this paper
• Case Report: Off-Label Liraglutide Use in Children With Wolfram Syndrome Type 1: Extensive Characterization of Four Patients

  2021cites this paper
• Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

  2021cites this paper
• Wolfram syndrome: new pathophysiological insights and therapeutic strategies

  2021cites this paper
• The Role of the UPR Pathway in the Pathophysiology and Treatment of Bipolar Disorder

  2021influential citation
• High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice.

  2021cites this paper
• Biological Pathways Associated with Neuroprogression in Bipolar Disorder

  2021cites this paper
• The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome

  2021cites this paper
• The Impact of Mutations in Wolframin on Psychiatric Disorders

  2021cites this paper
• Wolfram Syndrome: a Monogenic Model to Study Diabetes Mellitus and Neurodegeneration.

  2020cites this paper
• Endoplasmic reticulum stress and associated ROS in disease pathophysiology applications

  2020cites this paper
• Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome

  2020cites this paper
• The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

  2020cites this paper
• Current Landscape of Treatments for Wolfram Syndrome.

  2019cites this paper
• Endoplasmic Reticulum Stress: Implications for Neuropsychiatric Disorders

  2019cites this paper
• A cost of illness study evaluating the burden of Wolfram syndrome in the United Kingdom

  2019cites this paper
• Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

  2019cites this paper
• Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives

  2019cites this paper
• Molecular Mechanisms Linking ALS/FTD and Psychiatric Disorders, the Potential Effects of Lithium

  2019cites this paper
• Disturbed interactions between mitochondria and the endoplasmic reticulum : implications for human disease

  2017cites this paper
• Endoplasmic Reticulum Stress and Bipolar Disorder - Almost Forgotten Therapeutic Drug Targets in the Unfolded Protein Response Pathway Revisited.

  2016cites this paper
• Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome

  2016influential citation
• Evaluation of BDNF, Calcium Homeostasis and Cell Growth in Two Putative Disease Reporter Models of Bipolar Disorder

  2016cites this paper
• Endoplasmic Reticulum Stress and Associated ROS

  2016cites this paper
• Pathophysiology and gene therapy of the optic neuropathy in Wolfram Syndrome

  2016cites this paper
• Changes in the Peripheral Blood Gene Expression Profile Induced by 3 Months of Valproate Treatment in Patients with Newly Diagnosed Epilepsy

  2015cites this paper
• A patient-centered model of the action of psychotropic drugs

  2015cites this paper
• Impaired endoplasmic reticulum stress response in bipolar disorder: cellular evidence of illness progression.

  2014cites this paper
• LOODUS- JA TEHNOLOOGIATEADUSKOND MOLEKULAAR- JA RAKUBIOLOOGIA INSTITUUT

  2014cites this paper
• Initiation and developmental dynamics of Wfs1 expression in the context of neural differentiation and ER stress in mouse forebrain

  2014cites this paper
• Effect of Chronic Valproic Acid Treatment on Hepatic Gene Expression Profile in Wfs1 Knockout Mouse

  2014cites this paper
• LOODUS- JA TEHNOLOOGIATEADUSKOND MOLEKULAAR- JA RAKUBIOLOOGIA INSTITUUT ARENGUBIOLOOGIA ÕPPETOOL

  2013cites this paper
• Role of μ-opioid system in the formation of memory of placebo responses

  2013cites this paper
• Xenobiotic Perturbation of ER Stress and the Unfolded Protein Response

  2013cites this paper
• The role of the unfolded protein response in diabetes mellitus

  2013cites this paper
• Neurotrophins, inflammation and oxidative stress as illness activity biomarkers in bipolar disorder

  2013cites this paper
• Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion

  2012cites this paper
• Annual Research Review: Transgenic mouse models of childhood-onset psychiatric disorders.

  2011cites this paper
• A computational method for detecting multi-locus associations :an application to bipolar disorder

  2011cites this paper
• Luteolin shows an antidepressant-like effect via suppressing endoplasmic reticulum stress.

  2011cites this paper
• Transgenic Mouse Models of Childhood Onset Psychiatric Disorders

  2011cites this paper
• The endoplasmic reticulum protein folding factory and its chaperones: new targets for drug discovery?

  2011cites this paper
• Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin

  2011cites this paper
• Emerging drugs for amyotrophic lateral sclerosis

  2011cites this paper
• Visual Tuning Properties of Genetically Identified Layer 2/3 Neuronal Types in the Primary Visual Cortex of Cre-Transgenic Mice

  2011cites this paper
• The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies.

  2010cites this paper
• SILVA SÜTT Role of endocannabinoid system and Wfs1 in regulation of emotional behaviour: behavioural, pharmacological and genetic studies

  2010cites this paper
• AATF mediates anti-apoptotic effect of the unfolded protein response through transcriptional regulation of AKT1

  2009cites this paper
• Evidence Supporting a Role for Endoplasmic Reticulum Stress in the Development of Atherosclerosis in a Hyperglycaemic Mouse Model

  2009cites this paper