Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness

Manji, Husseini K.; Lenox, Robert H.

doi:10.1016/s0006-3223(99)00235-8

Cited by 222 publications

(192 citation statements)

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“…In addition, the platelet levels of PIP 2 and the PKC-␣ isozyme were significantly reduced in lithiumtreated bipolar patients compared with healthy control subjects (Soares et al 2000b). Similarly, chronic administration of lithium or valproate decreased the levels of membrane PKC ␣ and ⑀ isozymes in rat frontal cortex and hippocampus, immortalized hippocampal cells and PC12 cells (reviewed in Manji and Lenox 1999). These results together with the findings that CD151 acts as an anchoring protein for PI 4-K and activated PKC ␣ (Hemler 1998;Yauch et al 1998), raise an interesting possibility that these mood stabilizers, lithium in particular, may normalize the hyperfunctional phosphoinositide signaling pathways implicated in bipolar disorder, in part through down-regulation of CD151 expression.…”

Section: Discussionmentioning

confidence: 99%

“…However, significant progress has been made over the past decade with cumulative evidence indicating that modulation of postreceptor signaling mechanisms in critical regions of the brain may be essential to the mood stabilizing properties of this agent (reviewed in Jope 1999;Li et al 2000;Manji and Lenox 1999).…”

Section: The Latency In Onset Of Antimanic and Mood Stabilizing Effecmentioning

confidence: 99%

mentioning

confidence: 99%

“…Moreover, the delayed onset of therapeutic action of lithium has led to the hypothesis that regulation of gene expression may be important for its mood stabilizing effects (Jope 1999;Li et al 2000). In line with this hypothesis, several studies have demonstrated that chronic lithium treatment alters the expression of an array of genes, including G protein ␣ -subunits, adenylyl cyclase subtypes, neuropeptides (reviewed in Jope 1999;Li et al 2000;Manji and Lenox 1999), proapoptotic and antiapoptotic proteins (Chen and Chuang 1999), and synaptic secretory vesicle proteins (Cordeiro et al 2000). The modulatory effects of lithium on gene expression have been suggested to be mediated, at least in part, through the cAMP response element binding protein (CREB) or activator protein-1 (AP-1) transcriptional factor pathway (Ozaki and Chuang 1997;Asghari et al 1998;Yuan et al 1998).…”

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Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Hua

Green

Wong

et al. 2001

Neuropsychopharmacology

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The latency in onset of antimanic and mood stabilizing effects of lithium suggest that long-term neuronal adaptations mediated by changes in gene expression may be important to the therapeutic action of lithium treatment. Using differential display-polymerase chain reaction, several novel, hitherto unexpected lithium-regulated genes have been isolated, all of which would not have beenAlthough lithium is widely used in the treatment of acute mania and the prophylaxis for bipolar affective disorder, the cellular and molecular mechanisms underlying its therapeutic action remain unclear. However, significant progress has been made over the past decade with cumulative evidence indicating that modulation of postreceptor signaling mechanisms in critical regions of the brain may be essential to the mood stabilizing properties of this agent (reviewed in Jope 1999;Li et al. 2000;Manji and Lenox 1999).Many signal transduction cascades are known to induce long-term cellular responses through regulation of gene transcription. Moreover, the delayed onset of therapeutic action of lithium has led to the hypothesis that regulation of gene expression may be important for its mood stabilizing effects (Jope 1999;Li et al. 2000). In line with this hypothesis, several studies have demonstrated that chronic lithium treatment alters the expression of an array of genes, including G protein ␣ -subunits, adenylyl cyclase subtypes, neuropeptides (reviewed in Jope 1999;Li et al. 2000;Manji and Lenox 1999) NO . 5 et al. 2000). The modulatory effects of lithium on gene expression have been suggested to be mediated, at least in part, through the cAMP response element binding protein (CREB) or activator protein-1 (AP-1) transcriptional factor pathway (Ozaki and Chuang 1997;Asghari et al. 1998;Yuan et al. 1998). It is thus conceivable that other genes containing the consensus sequences for these transcription factors in their promoter region may also be the potential targets of lithium. Therefore, the identification of other lithium-regulated genes is important in better understanding the spectrum of cellular and molecular mechanisms that contribute to the therapeutic and/or side effects of this drug.Using differential display-polymerase chain reaction (ddPCR), several novel lithium-regulated genes have been identified that would not otherwise have been considered using a candidate gene approach. These novel lithium-regulated targets included 2 Ј , 3 Ј -cyclic nucleotide 3 Ј -phosphodiesterase type II (Wang and Young 1996), polyomavirus enhancer-binding protein 2 ␤ (Chen et al. 1999), nitrogen permease regulator 2 (Wang et al. 1999), aldolase A (Hua et al. 2000, and diphosphoinositol polyphosphate phosphohydrolase II (Hua et al. 2001). Unexpectedly, during the course of experiments amplifying the 5 Ј end of a putative lithium-regulated ddPCR fragment, we isolated another cDNA clone, a homolog of human/mouse transmembrane-4-superfamily (TM4SF) protein, CD151. The transcript levels of CD151 were significantly decreased in the rat frontal corte...

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Section: Discussionmentioning

confidence: 99%

Section: The Latency In Onset Of Antimanic and Mood Stabilizing Effecmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Hua

Green

Wong

et al. 2001

Neuropsychopharmacology

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“…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 and Lenox 1999). Therefore, it has been suggested by some investigators that PKC may be an important target for the action of mood stabilizers, such as lithium and valproate (Lenox and Manji 1998;Ikonomov and Manji 1999;Jope 1999).…”

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confidence: 99%

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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