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Inhibition of GSK3 by lithium, from single molecules to signaling networks

By Laure Freland and Jean-Martin Beaulieu


For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been shown to directly inhibit glycogen synthase kinase 3 alpha and beta (GSK3α and GSK3β). However in vivo, lithium also inhibits GSK3 by regulating other mechanisms like the formation of a signaling complex comprised of beta-arrestin 2 (βArr2) and Akt. Here, we provide an overview of in vivo evidence supporting a role for inhibition of GSK3 in some behavioral effects of lithium. We also explore how regulation of GSK3 by lithium within a signaling network involving several molecular targets and cell surface receptors [e.g., G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)] may provide cues to its relative pharmacological selectivity and its effects on disease mechanisms. A better understanding of these intricate actions of lithium at a systems level may allow the rational development of better mood stabilizer drugs with enhanced selectivity, efficacy, and lesser side effects

Topics: Neuroscience
Publisher: Frontiers Media S.A.
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    1. 138, 252–256. D eS a r n o ,P . ,L i ,X . ,a n dJ o p e ,R .S . (2002).Regulation ofAktandglycogen synthase kinase-3 beta phosphorylation by sodium valproate andlithium.Neuropharmacology 43,
    2. (2005). 3Li lithium metallotherapeutics,” in Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals
    3. (2006). A chaperonedependent GSK3beta transitional intermediate mediates activationloopautophosphorylation.
    4. (2002). A common mechanism of action for three mood-stabilizing drugs.
    5. (1996). A molecular mechanism for the effect of lithium on development.
    6. (2011). A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health.
    7. (2009). Akt/GSK3signaling in the action of psychotropic drugs.
    8. (2005). Alteration of lithium pharmacology through manipulation of phosphoadenosine phosphate metabolism.
    9. (2005). An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.
    10. (2008). Association between GSK-3beta -50T/C polymorphism and personality and psychotic symptoms in mood disorders. Psychiatry Res.
    11. (1998). Axin, a negative regulator of the Wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin.
    12. (2002). B l a n c o ,C . ,L a j e ,G . ,O l f s o n
    13. (2007). B o s w e l l ,S . ,M a y ,R .S . ,D a v i s
    14. (2008). Behavioral phenotypingstrategies formutantmice.
    15. (1990). Beta-arrestin: a protein that regulates beta-adrenergic receptor function.
    16. (2011). Beyond cAMP: the Regulation of Akt and GSK3 by dopamine receptors.
    17. (2010). Beyond desensitization: physiological relevance of arrestindependent signaling.
    18. (2011). C l o r e ,E .L . ,R i l e y ,M . ,R i c h a r d s
    19. (2010). Cell signaling by receptor tyrosine kinases.
    20. (2004). Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.
    21. (2008). Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C beta II in the diabetic fat tissue. A m .J .P h y s i o l .E n d o c r i n o l .
    22. (1999). Della R o c c a ,G .J . ,L i n ,F . ,K a w a k a t s u
    23. (2007). Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4splice-variant expression in the brain in schizophrenia.
    24. (2002). Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder?
    25. (2000). Efficacy of lithium in mania and maintenance therapy of bipolar disorder.
    26. (2012). Frontiers in Molecular Neuroscience
    27. (1998). Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta.
    28. (2004). G a i n e t d i n o v ,R .R . ,a n dC a r o n , Frontiers
    29. (2009). G e ,X . ,F r a n k ,C .L . ,M a d i s o n
    30. (2008). G h i s i ,V . ,W e t s e l
    31. G.(2008).Antagonism ofdopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics.
    32. (2004). glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation inbipolardepression.
    33. (1980). Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclicAMP-dependent protein kinase and phosphorylase kinase.
    34. (2011). Glycogen synthase kinase-3 in the etiology and treatment of mood disorders.
    35. (2004). Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium.
    36. (2011). Glycogen synthase kinase3 is essential for beta-arrestin-2 complex formation and lithiumsensitive behaviors in mice.
    37. (2011). GSK-3: functional Insights from Cell Biology and Animal Models.
    38. (2011). GSK3 and Alzheimer’s disease: facts and fiction.
    39. (2010). GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism.
    40. (2008). H e n n i g e ,A .M . ,L u t z ,S .Z . , H a r i n g ,H .U . ,S c h l e i c h e r
    41. (2004). In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3.
    42. (2004). In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain.
    43. (1993). Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growthfactor signalling.
    44. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediatedbyproteinkinaseB.Nature378,
    45. (2012). Inhibition of GSK3 by lithium, from single molecules to signaling networks.
    46. (2003). Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3.
    47. (2001). Judging a protein by more than its name:
    48. (2008). K a s s ,S . ,A g a m ,G . ,B e l m a k e r
    49. (2002). K i n g ,N . ,M a c c i a r d i ,F . ,a n d
    50. (2007). Lack of lithiumlike behavioral and molecular effects in IMPA2 knockout mice.
    51. (1974). Letter: lithium and magnesium-dependent enzymes.
    52. (1999). Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons.
    53. (2005). Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials.
    54. (1981). Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders.
    55. (1949). Lithium salts in the treatment of psychotic excitement.
    56. Lithiuminhibitsglycogen synthase kinase-3 activity and mimicswingless signalling in intact cells.
    57. (2009). Long-term lithium treatment in the prevention of suicidal behavior in bipolar disorder patients.
    58. (2008). Looking at lithium: molecular moods and complex behaviour.
    59. (2004). Magic shotguns versus magic bullets: selectively nonselective drugs for mood disorders and schizophrenia.
    60. (1998). Mechanism of activation and function of protein kinase
    61. (1994). Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation.
    62. (1993). Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation.
    63. (1990). Molecular cloning and expression of glycogen synthase kinase-3/factor A.
    64. (2001). Molecular targets of lithium action.
    65. (1989). Neural and developmental actions of lithium: a unifying hypothesis.
    66. (2009). Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1.
    67. P a n ,J .Q . ,L e w i s ,M .C . ,K e t t e r m a n ,J .
    68. (2012). paper pendingpublished:27January2012; accepted: 31
    69. (2010). Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models.
    70. (1997). Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action.
    71. (2010). Physiological regulation of Akt activity and stability.
    72. (2001). PKB/AKT: functional insights from genetic models.
    73. (2011). Quantification of receptor tyrosine kinase transactivation through direct dimerization and surface density measurements in single cells.
    74. (2004). Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on betacatenin in mouse hippocampus.
    75. (2007). Response to lithium augmentation in depression is associated with the glycogen synthase kinase 3-beta -50T/C single nucleotide polymorphism.
    76. (1996). Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization.
    77. (2002). Signaling networks in the pathophysiology and treatment of mood disorders.
    78. (2006). SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior.
    79. (1983). synthase from rabbit skeletal muscle; effect of insulin on the state of phosphorylation of the seven phosphoserine residuesinvivo.Eur.J.
    80. (2011). T a u r i s a n o ,P . ,R o m a n o
    81. (1994). The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro.
    82. (2008). The DISC locus in psychiatric illness.
    83. (1976). The dopamine hypothesis of schizophrenia: focus on the dopamine receptor.
    84. (2011). The physiology, signaling, and pharmacology of dopamine receptors.
    85. (2001). The renaissance of GSK3.
    86. (1954). The treatment of manic psychoses by the administration of lithium salts.
    87. (2001). v e s ,W .J . ,a n dH a r w o o d ,A .J .
    88. (2006). W e i ,S . ,J u n g ,S .Y . ,H u a n g
    89. (2006). What happened to lithium? Antidepressant augmentation in clinical settings.

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