Chronic lithium administration alters a prominent PKC substrate in rat hippocampus

Robert H. Lenox, David G. Watson, Jit Patel, John Ellis

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Abstract

The therapeutic effect of lithium in the treatment of bipolar disorder exhibits a significant delay in the onset of action and a persistence of efficacy beyond abrupt discontinuation of treatment. Lithium is known to alter receptor-coupled phosphoinositide second messenger pathway in brain, resulting in indirect changes in an endogenous activator of protein kinase C (PKC). Such evidence has suggested that PKC may be involved in the mechanism of action of lithium in the brain. PKC represents a site wherein long-term regulatory changes in cell function occur through the phosphorylation of specific phosphoproteins involved in processes including neurotransmitter release and receptor activation. In studies of rats exposed to lithium, however, we have found no significant effects of chronic administration on the relative activity, subcellular distribution, or activation of PKC in hippocampus. We did find a major reduction in the in vitro PKC mediated phosphorylation of two major substrates, 83 kDa and 45 kDa, in hippocampus of rats exposed to chronic lithium and maintaining clinically relevant therapeutic levels in brain. Using immunoblot analysis we have identified a known myristoylated alanine-rich C kinase substrate (MARCKS) at 83 kDa. In vivo levels of MARCKS in hippocampus were found to be significantly reduced after chronic lithium exposure. These findings persist in animals withdrawn from lithium, but are not apparent following acute treatment. In light of the potential role of PKC substrates such as MARCKS in signal transduction and the fact that there appear to be changes in the intracellular concentration of MARCKS that parallel the time course of clinical action of lithium, we suggest the possible involvement of these proteins in its mechanism of action in the treatment of bipolar disorder.

Original languageEnglish (US)
Pages (from-to)333-340
Number of pages8
JournalBrain research
Volume570
Issue number1-2
DOIs
Publication statusPublished - Jan 20 1992

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All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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