Chronic lithium administration alters a prominent PKC substrate in rat hippocampus

Lenox, Robert H.; Watson, David; Patel, Jit; Ellis, John E.

doi:10.1016/0006-8993(92)90598-4

Cited by 120 publications

(86 citation statements)

References 32 publications

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“…Another reason for delayed gene expression during lithium feeding to intact animals is the approximately 1-week half-life for lithium to reach a steady-state brain concentration, due to its slow penetration across the blood-brain barrier (Bosetti et al, 2002b). In this regard, lithium has been reported to target G-proteins (Li et al, 1993;Miki et al, 2001;Wang and Friedman, 1999), cyclic adenosine monophosphate (cAMP) (Mork, 1993;Mork and Geisler, 1995), protein kinase A (Mori et al, 1998), protein kinase C (PKC) (Manji et al, 1993(Manji et al, , 1996Soares et al, 2000) and its substrate MARCKS (Lenox et al, 1992;Watson and Lenox, 1996), glycogen synthase kinase-3 beta (GSK-3 b) (De Sarno et al, 2002), and activating protein 1 (AP-1) transcription factor (Ozaki and Chuang, 1997;Yuan et al, 1999). We reported that 6 weeks of lithium administration to rats, so as to produce therapeutically relevant plasma and brain lithium concentrations, resulted in reduced arachidonic acid (AA) turnover in brain phospholipids (Chang et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Administration of lithium causes the downregulation of MARCKS in rat hippocampus (Lenox et al 1992), and in immortalized hippocampal cells (Watson et al 1994;Watson and Lenox 1996;Wang et al 2000), suggesting a relationship between bipolar disorders and alteration in MARCKS. Although MARCKS has been studied in postmortem brain of suicide victims (McNarmara et al 1999), there have been no studies of MARCKS in patients with bipolar or unipolar disorders.…”

Section: Phospholipase C (Plc) and Protein Kinase C (Pkc) Are Importamentioning

confidence: 94%

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Pandey

Dwivedi

SridharaRao

et al. 2002

Neuropsychopharmacology

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Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PIdrolysis of the substrate, phosphatidyl inositol 4,5-bisphosphate (PIP 2 ), by the enzyme phospholipase C (PLC), resulting in the formation of two second messengers, inositol 1,4,5-trisphophate (IP 3 ) and diacylglycerol (DAG) (Berridge and Irvine 1989). IP 3 stimulates the release of intracellular calcium from the endoplasmic reticulum, and DAG stimulates the enzyme protein kinase C (PKC) (Nishizuka 1992), which is one of the major intracellular mediators of signals generated by the stimulation of cell surface receptors.Several studies indicate abnormalities of the PI signaling system in patients with unipolar or bipolar disorders. It has been reported that the hydrolysis of PIP 2 by several agonists, such as sodium fluoride (NaF) and GTP ␥ S, is altered in the postmortem brain of depressed Pacheco et al. 1996). PI signal transduction determined by serotonin (5HT)-, thrombin-, and NaF-stimulated IP formation has also been reported to be increased in platelets of depressed patients (Mikuni et al. 1991;Karege et al. 1996). These abnormalities may be related to abnormalities in receptors, such as 5HT 2A , 5HT 2C , muscarinic M 1 and M 2 , or ␣ 2 adrenergic receptors linked to the PI signaling system or to abnormal levels of substrates, such as PIP 2 , or to components of the signaling cascade, such as G-proteins, PKC, or PLC. Abnormalities in 5HT 2A (Pandey et al. 1995), ␣ 2 adrenergic receptors (Pandey et al. 1990), G-proteins (Garcia-Sevilla et al. 1997Karege et al. 1998;Gurguis et al. 1999), and levels of PIP 2 , a substrate for PI-PLC (Brown et al. 1993;Soares and Mallinger 1996;Soares et al. 1999), have been reported in platelets of unipolar and/or bipolar patients. PLC and PKC are two crucial components of the PI signaling system. Both PKC and PLC have been shown to be involved in a variety of physiological functions, such as synthesis, release, and reuptake of neurotransmitters, neuronal development, transcription, longterm potentiation (LTP), and behavioral responses (Nishizuka 1992). Although the role of PLC in affective disorders has not been fully investigated, some studies have shown abnormalities of PLC in depression and suicide Pandey et al. 1999). On the other hand, very few studies have examined the role of PKC in bipolar or unipolar disorders, although PKC has been implicated in the pathophysiology of bipolar disorders. For example, it has been reported that PKC activity as well as translocation of PKC from cytosol to membrane are increased in platelets of bipolar patients and that lithium treatment alters the activity of PKC in platelets (Friedman et al. 1993;Wang et al. 1999). Further evidence for the involvement of PKC in bipolar disorders is derived from observations that lithium exerts significant effects on PKC in a number of cell systems, including central nervous system (CNS) (Manji et al. 1993(Manji et al. , 1995Manji ...

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“…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. 102,103 This response however is complex.…”

Section: Calcium Signalingmentioning

confidence: 99%

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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Chronic lithium administration alters a prominent PKC substrate in rat hippocampus

Cited by 120 publications

References 32 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

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

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

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