Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients

Department of Pharmacology and Psychiatry, MCP-Hahnemann School of Medicine, Philadelphia, PA, USA.
Journal of Psychiatric Research (Impact Factor: 3.96). 03/1999; 33(2):171-9. DOI: 10.1016/S0022-3956(98)90057-7
Source: PubMed


recent investigations have suggested that the phosphoinositide (PI) signal transduction system may be involved in the pathophysiology of bipolar affective disorders. Earlier studies in our laboratory have implicated altered PKC-mediated phosphorylation in bipolar affective disorder and in the clinical action of lithium. In the present study, we compared PKC activity and its translocation in platelets from subjects with bipolar affective disorder and three other groups.
subjects included 44 with bipolar disorder (acute manic episode), 25 with acute major depression, 23 with schizophrenia in acute exacerbation and 43 controls free of personal or family history of an Axis I disorder. Blood platelet membrane and cytosol PKC activity was measured before and after in vitro stimulation with serotonin (5-HT), thrombin and the direct PKC activator, PMA. In addition, we examined 5-HT-, thrombin- and PMA-elicited translocations of PKC isozymes from cytosol to the membrane in platelets of control subjects.
in the basal state, manic subjects demonstrated higher membrane PKC activity than depressive and control subjects. The ratio of membrane to cytosol PKC activity was significantly higher in manic (1.10), as compared to control (0.84), depressed (0.93) or schizophrenic (0.93) subjects. Stimulation of platelets with 5-HT in vitro, resulted in greater membrane to cytosol ratio in the manic subjects compared to the three other groups. The responsiveness of platelets to PMA and thrombin was greater for manic subjects than for depressed and schizophrenic subjects, but not greater than the controls. In this measure both the schizophrenic and depressive groups were less active than controls. The results also demonstrate that platelets contain alpha-, beta-, delta- and zeta-PKC isozymes. While alpha- and beta-PKC isoforms were translocated from cytosol to membrane in response to serotonin, PMA and thrombin, serotonin also elicited the redistribution of delta-PKC and thrombin also activated zeta-PKC.
the results demonstrate that a heightened PKC-mediated signal transduction is associated with acute mania and suggest a decreased transduction in patients with unipolar depression or schizophrenia.

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    • "In accordance with our results, Szabo et al. (2009) observed increased phosphorylation of MARCKS, another PKC substrate, in the frontal cortexes of SD rats. Together, these results are consistent with studies revealing a hyperactivity of the PKC pathway in platelets of bipolar patients in a manic phase (Friedman et al., 1993; Hahn and Friedman, 1999; Wang et al., 1999). We subsequently investigated whether inhibition of PKC may be able to block the manic-like behaviors in the SD model. "
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    ABSTRACT: Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania. Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control. We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD. Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(2). DOI:10.1093/ijnp/pyu031 · 4.01 Impact Factor
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    • "Postmortem studies have demonstrated that membrane-associated PKC and the stimulation-induced translocation of the cytosolic enzyme to the membrane increased in the frontal cortex of patients with bipolar disorder [22], [23]. A significant increase in membrane-associated platelet PKC activity has been demonstrated in manic patients, while enhanced PKC activity during mania is suppressed by mood-stabilizer treatments [24], [25], [26]. In comparison, decreased PKC activity and PKCβI and βII levels, but not PKCα or PKCζ, in the membrane and cytosol fractions of platelets from medication-free pediatric patients with bipolar disorder has been reported [27]. "
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    ABSTRACT: Reports indicate that PDLIM5 is involved in mood disorders. The PDLIM5 (PDZ and LIM domain 5) gene has been genetically associated with mood disorders; it's expression is upregulated in the postmortem brains of patients with bipolar disorder and downregulated in the peripheral lymphocytes of patients with major depression. Acute and chronic methamphetamine (METH) administration may model mania and the evolution of mania into psychotic mania or schizophrenia-like behavioral changes, respectively. To address whether the downregulation of PDLIM5 protects against manic symptoms and cause susceptibility to depressive symptoms, we evaluated the effects of reduced Pdlim5 levels on acute and chronic METH-induced locomotor hyperactivity, prepulse inhibition, and forced swimming by using Pdlim5 hetero knockout (KO) mice. The homozygous KO of Pdlim5 is embryonic lethal. The effects of METH administration on locomotor hyperactivity and the impairment of prepulse inhibition were lower in Pdlim5 hetero KO mice than in wild-type mice. The transient inhibition of PDLIM5 (achieved by blocking the translocation of protein kinase C epsilon before the METH challenge) had a similar effect on behavior. Pdlim5 hetero KO mice showed increased immobility time in the forced swimming test, which was diminished after the chronic administration of imipramine. Chronic METH treatment increased, whereas chronic haloperidol treatment decreased, Pdlim5 mRNA levels in the prefrontal cortex. Imipramine increased Pdlim5 mRNA levels in the hippocampus. These findings are partially compatible with reported observations in humans, indicating that PDLIM5 is involved in psychiatric disorders, including mood disorders.
    PLoS ONE 04/2013; 8(4):e59320. DOI:10.1371/journal.pone.0059320 · 3.23 Impact Factor
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    • "One of the major lines of evidence suggesting the involvement of PKC in the pathophysiology of bipolar disorders is derived from the observation that mood stabilizing drugs, such as lithium or valproic acid (VPA), cause changes in the activity of PKC and the expression of PKC isozymes, both under in-vitro and ex-vivo conditions (Jope, 1999; Manji et al., 1993; Manji & Lenox, 1994; Morishita & Watanabe, 1994), thus suggesting that alterations in PKC may be involved in the pathophysiology of bipolar disorders (Friedman et al., 1993; Ikonomov & Manji, 1999; Manji et al., 1995; Manji & Lenox, 1999; Wang et al., 1999; Pandey et al., 2002). We therefore examined if pharmacotherapy with mood stabilizing drugs and/or clinical improvement are associated with changes in PKC activity or in the expression of PKC isozymes in the platelets of PBD patients. "
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    ABSTRACT: Pediatric bipolar disorder (PBD) is a major public health concern, however, its neurobiology is poorly understood. We, therefore, studied the role of protein kinase C (PKC) in the pathophysiology of bipolar illness. We determined PKC activity and immunolabeling of various PKC isozymes (i.e., PKC alpha, PKC betaI, PKC betaII, and PKC delta) in the cytosol and membrane fractions of platelets obtained from PBD patients and normal control subjects. PKC activity and PKC isozymes were also determined after 8 weeks of pharmacotherapy of PBD patients (n=16) with mood stabilizers. PKC activity and the protein expression of PKC betaI and betaII, but not PKC alpha or PKC delta, were significantly decreased in both membrane as well as cytosol fractions of platelets obtained from medication-free PBD patients compared with normal control subjects. Eight weeks of pharmacotherapy resulted in significantly increased PKC activity but no significant changes in any of the PKC isozymes in PBD patients. These results indicate that decreases of specific PKC isozymes and decreased PKC activity may be associated with the pathophysiology of PBD and that pharmacotherapy with mood stabilizing drugs results in an increase and normalization of PKC activity along with improvement in clinical symptoms.
    Journal of Psychiatric Research 02/2008; 42(2):106-16. DOI:10.1016/j.jpsychires.2006.11.004 · 3.96 Impact Factor
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