Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients.

Abstract

Dysregulated protein kinase C (PKC) distribution and activation, and abnormal receptor-G protein coupling, have been implicated in the pathophysiology of bipolar affective disorder (BD). 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), 1 microM 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 [35S]GTPgammaS binding to membrane Galpha 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 [35S]GTPgammaS binding to Galpha proteins was detected in BD manic but not in schizophrenic patients although basal [35S]GTPgammaS 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.

• Authors: Chang-Gyu Hahn, Umapathy, Hoau-Yan Wang, Ramesh Koneru, Douglas F Levinson, Eitan Friedman
• Journal: Journal of psychiatric research (J Psychiatr Res) Vol. 39 Issue 4 Pg. 355-63 (Jul 2005) ISSN: 0022-3956 [Print] England
• PMID: 16044535 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimanic Agents
• Valproic Acid
• Protein Kinase C
• GTP-Binding Proteins
• Lithium Chloride

Topics

• Adult
• Antimanic Agents (pharmacology, therapeutic use)
• Bipolar Disorder (drug therapy, physiopathology)
• Blood Platelets (physiology)
• Enzyme Activation
• Female
• GTP-Binding Proteins (physiology)
• Humans
• Lithium Chloride (pharmacology, therapeutic use)
• Male
• Protein Kinase C (metabolism)
• Schizophrenia (drug therapy, physiopathology)
• Signal Transduction
• Valproic Acid (pharmacology, therapeutic use)