Protein kinase C in platelets of depressed patients

Pandey, Ghanshyam N.; Dwivedi, Yogesh K.; Kumari, Ranjana; Janicak, Philip G.

doi:10.1016/s0006-3223(97)00535-0

Cited by 43 publications

(26 citation statements)

References 14 publications

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“…In particular, these alterations might be a consequence of increased PI levels (Silverstone et al, 2005) or Ga q/11 and PLC immunoreactivity (Mathews et al, 1997). An elevated PKC signalling activity has also been reported in platelets (Wang et al, 1999;Pandey et al, 1998) and brain samples from depressed patients. A further confirmation of this hypothesis is given by the observation that antidepressant drugs from different classes down-regulate the PIePKC signal transduction pathway by reducing PLC expression (Dwivedi et al, 2002), desensitising Ga q -coupled receptor-generated PLCmediated hydrolysis of PIP 2 (Dyck and Boulton, 1989;Pandey et al, 1991) or decreasing PKC activity (Mann et al, 1995;Morishita and Watanabe, 1997) in animal and human studies.…”

Section: Introductionmentioning

confidence: 74%

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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Section: Introductionmentioning

confidence: 74%

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

Galeotti¹,

Ghelardini²

2011

Neuropharmacology

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“…We had previously reported an increase in PKC binding sites using 3 H-phorbol dibutyrate as the ligand in the cytosol but not in the membrane fraction of platelets from unipolar patients (Pandey et al 1998). The reason for this discrepancy is not clear, but it could have various explanations; for exampe, some reports suggest that 3 H-PDBU Phorbol dibutyrate also binds to receptors other than PKC, including n-chimerin and Unc-13 (Hall et al 1990;Wilkinson and Hallam 1994).…”

Section: Discussionmentioning

confidence: 96%

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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“…[30][31][32][33][34][35][36][37][38][39] Alternatively, the observed modifications may reflect adaptive responses to other reported dysfunctions in cell signaling of depressed patients such as Ca 2+ signaling and the phosphoinositides cycle, including protein kinase C. [40][41][42][43][44][45][46] These findings alone or in combination may contribute to explain the reason why PKA and Rap1 are altered in major depression, but the molecular mechanisms by which these modifications occur remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase A and Rap1 levels in platelets of untreated patients with major depression

et al. 2000

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We have recently reported altered levels of protein kinase A and Rap1 in patients with bipolar disorder. The purpose of the current investigation was to assess the levels of these proteins in platelets from untreated euthymic and depressed patients with major unipolar depression. Platelets were collected from 45 drug-free unipolar patients (13 euthymic and 32 depressed) and 45 healthy subjects. The levels of protein kinase A and Rap1 were assessed by Western blot analysis, immunostaining and computer-assisted imaging. The immunolabeling of the regulatory subunit type II of protein kinase A and that of Rap1 was significantly lower in untreated depressed patients compared with untreated euthymic patients and healthy subjects. No significant differences were found in the immunolabeling of both the regulatory type I and the catalytic subunits of protein kinase A among groups. Levels of the regulatory subunit type II of protein kinase A and Rap1 are altered in platelets of unipolar depressive patients. These findings may provide new insight about the relationship between components of cAMP signaling and affective disorders. Molecular Psychiatry (2001) 6, 44-49.

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Protein kinase C in platelets of depressed patients

Cited by 43 publications

References 14 publications

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

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

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

Protein kinase A and Rap1 levels in platelets of untreated patients with major depression

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