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, Ghanshyam N.; Dwivedi, Yogesh K.; SridharaRao, Jagadeesh; Ren, Xinguo; Janicak, Philip G.; Sharma, Rajiv P.

doi:10.1016/s0893-133x(01)00327-x

Cited by 65 publications

(65 citation statements)

References 51 publications

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“…In a meta-analysis of 8,700 patients, both unipolar depression and BD were found to be associated with suicidality and gene locus for PKCε [170]. Moreover, using the convergent functional genomics approach, MARCKS, a PKC substrate [171], was found to be one of the 6 peripheral biomarkers that predict past and future hospitalization in relation to suicidality in patients with BD [172]. This observation further implicates hyperactive PKC signaling in the etiopathogenesis of BD.…”

Section: Geneticsmentioning

confidence: 99%

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: Geneticsmentioning

confidence: 99%

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

et al. 2017

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“…In contrast to the hypothesis of an over-stimulated PI cascade, it has been suggested that a hypofunctionality, rather than a hyperactivity, of the PIePKC pathway might be related to affective disorders. Studies performed in platelets and human brain samples reported no difference (Coull et al, 2000) or decreases in indices of PI or PKC signalling (Jope et al, 1996;Pandey et al, 2002) in patients suffering from bipolar or major depressive disorders. Specifically, a decreased activity and expression of PLC and PKC have been observed in teenage suicide victims (Pandey et al, 1999(Pandey et al, , 2004.…”

Section: Introductionmentioning

confidence: 93%

Antidepressant phenotype by inhibiting the phospholipase Cβ1 – Protein kinase Cγ pathway in the forced swim test

Galeotti¹,

Ghelardini²

2011

Neuropharmacology

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a b s t r a c tAlthough great advances have recently been made in the study of signal transduction, the pathogenesis of affective disorders is still unknown. There is mounting evidence suggesting that elevated phosphoinositideeprotein kinase C (PIePKC) signal transduction pathway may be a pathophysiological feature of bipolar and major depressive disorders. The aim of the present study was to further investigated the phospholipase Ceprotein kinase C (PLCePKC) cascade by evaluating the effect produced by an acute blockade of this intracellular pathway at PLC and PKC level. Adult male mice were administered with pharmacological inhibitors of PLC or PKC and then subjected to the forced swim test (FST), an animal model which emulates the behavioural despair paradigm of depression. In this study we also tested the hypothesis that it might be possible to selectively modulate depressive behaviour by inhibiting the expression of specific PLC and PKC isoforms by means of specific antisense oligonucleotides (aODNs). Administration of the PLC inhibitors neomycin and U73122 as well as of the PKC inhibitors calphostin C and chelerytrine dose-dependently reduced the immobility time in the FST producing an antidepressant-like behaviour. Selective knockdown of the PLCb 1 and PKCg isoforms also induced an antidepressant phenotype. Conversely, the inhibition of the expression of PLCb 3 was unable to modify the immobility time values. The PLC and PKC modulators used, at the highest effective doses, altered neither locomotor activity nor motor coordination. We demonstrate that selective blockade of PLCb 1 ePKCg signalling pathway produces an antidepressant-like phenotype in mice.

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“…It seems also relatively clear that treating mania with a mood stabilizer can reverse the enhancement of platelet PKC activity along with improving the mood in the same patients [90,91]. However, data become more discrepant when different mood states are mixed in the same BPD group (manic, mixed, and depressed states) [92][93][94]. Regarding MDD, two out of three studies reported no change in PKC activity, neither in the membrane nor in the cytosolic fractions [89,94].…”

Section: Abnormalities Of the Pkc System In Patients With Mood Disordersmentioning

confidence: 99%

A Role for the PKC Signaling System in the Pathophysiology and Treatment of Mood Disorders: Involvement of a Functional Imbalance?

et al. 2011

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Mood disorders, such as bipolar and major depressive disorders, are frequent, severe, and often disabling neuropsychiatric diseases affecting millions of individuals worldwide. Available mood stabilizers and antidepressants remain unsatisfactory because of their delayed and partial therapeutic efficacy. Therefore, the development of targeted therapies, working more rapidly and being fully effective, is urgently needed. In this context, the protein kinase C (PKC) signaling system, which regulates multiple neuronal processes implicated in mood regulation, can constitute a novel therapeutic target. This paper reviews the currently available knowledge regarding the role of the PKC signaling pathway in the pathophysiology of mood disorders and the therapeutic potential of PKC modulators. Current antidepressants and mood stabilizers have been shown to modulate the PKC pathway, and the inhibition of this intracellular signaling cascade results in antimanic-like properties in animal models. Disrupted PKC activity has been found both in postmortem brains and platelet from patients with mood disorders. Finally, the PKC inhibitor tamoxifen has recently demonstrated potent antimanic properties in several clinical trials. Overall, emerging data from preclinical and clinical research suggest an imbalance of the PKC signaling system in mood disorders. Thus, PKC may be a critical molecular target for the development of innovative therapeutics.

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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

Cited by 65 publications

References 51 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

Antidepressant phenotype by inhibiting the phospholipase Cβ1 – Protein kinase Cγ pathway in the forced swim test

A Role for the PKC Signaling System in the Pathophysiology and Treatment of Mood Disorders: Involvement of a Functional Imbalance?

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