Lithium regulates PKC‐mediated intracellular cross‐talk and gene expression in the CNS <i>in vivo</i>

Chen, Guang; Masana, Monica I.; Manji, Husseini K.

doi:10.1034/j.1399-5618.2000.20303.x

Cited by 82 publications

(43 citation statements)

References 161 publications

(199 reference statements)

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“…Later, the levels of membrane-associated PKC were shown to decrease after exposure to lithium and valproic acid, in vitro [38] and in vivo [39,40]. These observations were corroborated in humans when chronic treatment with lithium decreased PKC signaling in euthymic patients with BD [41].…”

Section: Pkc Translocation and Activitymentioning

confidence: 94%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

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Section: Pkc Translocation and Activitymentioning

confidence: 94%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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“…Lithium has been used as a mood-stabilizing drug for the treatment of manic episodes and depression. The targets of lithium are varied and clearly point to lithium modifying signal transduction pathways (Chen et al, 2000;Shamir et al, 2003;Tsuji et al, 2003), which would alter the complement of active transcription factors in the cell (Ikonomov and Manji, 1999). We demonstrate that the intron 2 VNTR is a target for mediating a transcriptional response to LiCl via (at least in part) the transcription factors CTCF and YB-1.…”

Section: Introductionmentioning

confidence: 90%

Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat

Roberts

Scott²,

Howard³

et al. 2007

J. Neurosci.

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The serotoninergic pathways are possible targets for the action of lithium, a therapeutic agent for treatment of bipolar affective disorders. This study aimed to investigate the molecular mechanisms regulating human serotonin transporter gene (SLC6A4) expression by lithium and, specifically, the role of the variable number tandem repeat (VNTR) polymorphic region in intron 2, which is potentially a predisposing genetic factor for bipolar affective disorders. We demonstrated that addition of lithium to human JAr cells led to changes in the levels of SLC6A4 mRNA and protein. Additional investigations revealed that the intron 2 VNTR domain was a potential target for mediation of a transcriptional response to lithium. Properties of two transcription factors, CCCTC binding protein (CTCF) and Y-box binding protein 1 (YB-1), previously shown to be involved in the regulation of SLC6A4 VNTR, were found to be modulated by LiCl. Thus, levels of CTCF and YB-1 mRNA and protein were altered in vivo in response to LiCl. Furthermore, CTCF and YB-1 showed differential binding to the polymorphic alleles of the VNTR on exposure to LiCl. Our data suggest a model in which differential binding of CTCF and YB-1 to the allelic variants of the intron 2 VNTR can be regulated by lithium and in part result in differential and even aberrant expression of SLC6A4. Our study of the regulation of the SLC6A4 VNTR by lithium may improve the understanding of psychiatric disorders and enable the development of novel therapies for conditions such as bipolar affective disorder to target only the at-risk allele.

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“…39 In BD patients, lithium also reduced Gas, and the anticonvulsants sodium valproate and carbamazepine reduced CREB (Table 1). The observation that multiple sites are involved in the action of lithium firmly suggests that its outcome is the result of a balance between various modulatory effects, rather than a single mechanism.…”

Section: The Signal Transduction Cascadesmentioning

confidence: 99%

Affective disorders, antidepressant drugs and brain metabolism

2003

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There is increasing evidence that affective disorders are associated with dysfunction of neurotransmitter postsynaptic transduction pathways and that chronic treatment with clinically active drugs results in adaptive modification of these pathways. Despite the close dependence of signal transduction on adenosine triphosphate (ATP) availability, the changes in energy metabolism in affective disorders are largely unknown. This question has been indirectly dealt with through functional imaging studies (PET, SPECT, MRS). Despite some inconsistencies, PET and SPECT studies suggest low activity in cortical (especially frontal) regions in depressed patients, both unipolar and bipolar, and normal or increased activity in the manic pole. Preliminary MRS studies indicate some alterations in brain metabolism, with reduced creatine phosphate and ATP levels in the brain of patients with affective disorders. However, the involvement of the energy metabolism in affective disorders is still debated. We propose direct neurochemical investigations on mitochondrial functional parameters of energy transduction, such as the activities of (a) the enzymatic systems of oxidative metabolic cycle (Kreb's cycle); (b) the electron transfer chain; (c) oxidative phosphorylation, and (d) the enzyme activities of ATP-requiring ATPases. These processes should be studied in affective disorders and in animals treated with antidepressant drugs or lithium.

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Lithium regulates PKC‐mediated intracellular cross‐talk and gene expression in the CNS in vivo

Cited by 82 publications

References 161 publications

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat

Affective disorders, antidepressant drugs and brain metabolism

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