Journal
JOURNAL OF PSYCHIATRIC RESEARCH
Volume 39, Issue 4, Pages 355-363Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jpsychires.2004.10.007
Keywords
bipolar disorder; schizophrenia; protein kinase C; G protein; lithium; valproic acid
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Funding
- NIMH NIH HHS [MH60964] Funding Source: Medline
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Dysregulated protein kinase C (PKC) distribution and activation, and abnormal receptor-G protein coupling, have been implicated in the pathophysiology of bipolar affective disorder (BID). The therapeutic effectiveness of lithium has also been correlated with its ability to reduce PKC activation and G protein-mediated signaling. We examine the cellular distribution and activation of PKC and receptor-G protein coupling in blood platelets from normal controls, patients with BD mania or schizophrenia during treatment-free state, and after lithium or valproic acid administration. PKC activity was measured under basal and 50 nM phorbol 12-myristate, 13-acetate (PMA), I mu M serotonin or 0.5 U/ml thrombin-stimulated conditions. The coupling of G proteins to serotonin or thrombin receptors were assessed by serotonin or thrombin-mediated [S-35]GTP gamma S binding to membrane G alpha proteins. The results demonstrate that membrane-associated PKC activity and stimulus-induced PKC translocation are increased in BD manic, whereas stimulus-elicited PKC translocation is attenuated in schizophrenic patients. Lithium and valproic acid treatments attenuated the stimulus-induced PKC translocations to a similar degree and decreased PKC activity in both cytosolic and membranous fractions after two weeks of drug administration. An increase in 5-HT or thrombin stimulated [S-35]GTP gamma S binding to Got proteins was detected in BID manic but not in schizophrenic patients although basal [S-35]GTP gamma S binding was not different across the diagnostic groups. Lithium and valproic acid treatments similarly reduced receptor-G protein coupling with comparable time courses. Thus, increased membrane-associated PKC, cytosol to membrane PKC translocation and receptor-G protein coupling in platelets of BD manic patients were alleviated by lithium or valproic acid treatments. (c) 2004 Elsevier Ltd. All rights reserved.
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