Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients.
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.
Hahn
Chang-Gyu
CG
Medical College of Pennsylvania, Philadelphia, PA, USA.
Umapathy
Wang
Hoau-Yan
HY
Koneru
Ramesh
R
Levinson
Douglas F
DF
Friedman
Eitan
E
D000328:Adult; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000503:physiopathology*; D001792:Blood Platelets / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology*; D015398:Signal Transduction; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use*
D018692:Antimanic Agents; D014635:Valproic Acid; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D018021:Lithium Chloride