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

Chang Gyu Hahn, Umapathy, Hoau Yan Wang, Ramesh Koneru, Douglas F. Levinson, Eitan Friedman

Research output: Contribution to journalArticlepeer-review

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 μM 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]GTPγS binding to membrane Gα 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]GTPγS binding to Gα proteins was detected in BD manic but not in schizophrenic patients although basal [35S]GTPγS 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.

Original languageEnglish
Pages (from-to)355-363
Number of pages9
JournalJournal of Psychiatric Research
Volume39
Issue number4
DOIs
StatePublished - Jul 2005
Externally publishedYes

Keywords

  • Bipolar disorder
  • G protein
  • Lithium
  • Protein kinase C
  • Schizophrenia
  • Valproic acid

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