Lithium treatment inhibits protein kinase C translocation in rat brain cortex

Wang, Hoau-Yan; Johnson, Gerard P.; Friedman, Eitan

doi:10.1007/s002130100834

Cited by 42 publications

(34 citation statements)

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“…This absence of change in total PKC activity was ascribed to a high abundance of PKC g, a neuron-specific PKC, which is the major contributor to total PKC activity, thus masking changes in activities of the other PKC isoforms (Wang et al, 2001). The lack of effect on basal activity by lithium that we observed in this study may be due to the contribution of activity by other PKC isoforms, which masked the changes in the PKC a and PKC e activities.…”

Section: Discussioncontrasting

confidence: 43%

“…Earlier studies indicated that chronic lithium treatment altered PKC isoforms in rat frontal cortex, without changing total tissue PKC activity (Wang et al, 2001). This absence of change in total PKC activity was ascribed to a high abundance of PKC g, a neuron-specific PKC, which is the major contributor to total PKC activity, thus masking changes in activities of the other PKC isoforms (Wang et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Postmortem studies have also reported increased membrane-associated PKC and increased translocation of PKC isoforms from cytosol to membrane in response to phorbol 12-myristate 13-acetate in frontal cortex of brains from bipolar disorder compared with control subjects (Wang and Friedman, 1996). In the rat brain, chronic lithium treatment reduced cytosolic PKC a and PKC d and increased membranal PKC z immunoreactivities, without altering total PKC activity (Wang et al, 2001). Chronic lithium also suppressed the translocation of PKC a and of other PKC isoforms in rat brain (Hahn and Friedman, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

Rao

Rapoport

Bosetti

2005

Neuropsychopharmacol

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Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A 2 (cPLA 2 ), without affecting secretory sPLA 2 or Ca 2 þ -independent iPLA 2 . We investigated whether transcription factors known to regulate cPLA 2 gene expression are modulated by chronic lithium treatment. Male Fischer-344 rats were fed a LiCl-containing diet for 6 weeks to produce a therapeutically relevant brain lithium concentration. Control animals were fed a LiCl-free diet. Using a gelshift assay, we found that LiCl significantly decreased activating protein 2 (AP-2)-binding activity, and protein levels of the AP-2 a and AP-2 b but not of the AP-2 g subunits in the frontal cortex. Activating protein 1 (AP-1)-binding activity was increased, whereas glucocorticoid response element, polyoma enhancer activator 3, and nuclear factor kappa B DNA-binding activities were not changed significantly. Since both cPLA 2 and AP-2 can be activated by protein kinase C (PKC), we examined the frontal cortex protein levels of PKC a and PKC e, as well as AA-dependent PKC activity. The protein levels of PKC a and PKC e were decreased significantly, as was AA-dependent PKC activity, in the lithium-treated compared to control rats. Our results suggest that the reported decrease in brain gene expression of cPLA 2 by chronic lithium may be mediated by reduced AP-2 transcriptional activity, and that decreased expression of PKC a and PKC e contributes to lowering the AP-2 activity.

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Section: Discussioncontrasting

confidence: 43%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

Rao

Rapoport

Bosetti

2005

Neuropsychopharmacol

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“…98 PKC activation requires translocation to the membrane where it interacts with the receptor for activated C-kinase-1 (RACKS-1) protein. Li þ treatment reduces this translocation, consistent with reduced generation of DAG from PdtIns(4,5)P 2 , 99 and increased association with RACK-1 has been observed in post-mortem brains from bipolar patients. 100 Chronic Li þ treatment in rats decreases both PKC activity and phosphorylation of a PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS), 101 an effect reversed by addition of myoinositol.…”

Section: Calcium Signalingsupporting

confidence: 73%

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

2004

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Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules. Over the last 35 years, a series of biochemical and cell biological experiments have shown that lithium (Li þ ) reduces the cellular concentration of myo-inositol and as a consequence attenuates signaling within the cell. Based on these observations, inositol-depletion was proposed as a therapeutic mechanism in the treatment of bipolar mood disorder. Recent results have added significant new dimensions to the original hypothesis. However, despite a number of clinical studies, this hypothesis still remains to be either proven or refuted. In this review of our current knowledge, I will consider where the inositol-depletion hypothesis stands today and how it may be further investigated in the future.

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“…The chronic LiCl diet of this study is reported to reduce global brain mRNA, protein and activity levels of cPLA 2 in rats, but not to affect expression of sPLA 2 or iPLA 2 (Bosetti et al, 2002a, b;Chang and Jones, 1998;Rapoport and Bosetti, 2002;Rintala et al, 1999;Weerasinghe et al, 2004). Its cPLA 2 effect may be due a lithium-induced downregulation of Ca 2 + -dependent PKC, to reduce expression of PKC-dependent AP-2, which regulates cPLA 2 transcription (Rao et al, 2005;Wang et al, 2001). Consistent with selective cPLA 2 targeting, the LiCl diet reduces incorporation and turnover rates of AA but not of DHA in brain phospholipids of unanesthetized rats (Chang et al, 1996).…”

Section: Discussionmentioning

confidence: 65%

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

Basselin

Chang

Bell

et al. 2005

Neuropsychopharmacol

103

132

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It has been proposed that lithium is effective in bipolar disorder (BD) by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate receptors (NMDARs). To test this hypothesis and to see if the neurotransmission could involve the NMDARmediated activation of phospholipase A 2 (PLA 2 ), to release arachidonic acid (AA) from membrane phospholipid, we administered subconvulsant doses of NMDA to unanesthetized rats fed a chronic control or LiCl diet. We used quantitative autoradiography following the intravenous injection of radiolabeled AA to measure regional brain incorporation coefficients k* for AA, which reflect receptormediated activation of PLA 2 . In control diet rats, NMDA (25 and 50 mg/kg i.p.) compared with i.p. saline increased k* significantly in 49 and 67 regions, respectively, of the 83 brain regions examined. The regions affected were those with reported NMDARs, including the neocortex, hippocampus, caudate-putamen, thalamus, substantia nigra, and nucleus accumbens. The increases could be blocked by pretreatment with the specific noncompetitive NMDA antagonist MK-801 ((5R,10S)-( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate) (0.3 mg/kg i.p.), as well by a 6-week LiCl diet sufficient to produce plasma and brain lithium concentrations known to be effective in BD. MK-801 alone reduced baseline values for k* in many brain regions. The results show that it is possible to image NMDA signaling via PLA 2 activation and AA release in vivo, and that chronic lithium blocks this signaling, consistent with its suggested mechanism of action in BD.

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Lithium treatment inhibits protein kinase C translocation in rat brain cortex

Cited by 42 publications

References 2 publications

Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

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