Long-term action of lithium: a role for transcriptional and posttranscriptional factors regulated by protein kinase C.
Lithium, a simple monovalent cation, represents one of psychiatry's most important treatments and is the most effective treatment for reducing both the frequency and severity of recurrent affective episodes. Despite extensive research, the underlying biologic basis for the therapeutic efficacy this drug remains unknown, and in recent years, research has focused on signal transduction pathways to explain lithium's efficacy in treating both poles of manic-depressive illness. Critical to attributions of therapeutic relevance to any observed biochemical effect, however, is the observation that the characteristic prophylactic action of lithium in stabilizing the profound mood cycling of bipolar disorder requires a lag period for onset and is not immediately reversed upon discontinuation of treatment. Biochemical changes requiring such prolonged administration of a drug suggest alterations at the genomic level but, until recently, little has been known about the transcriptional and posttranscriptional factors regulated by chronic drug treatment, although long-term changes in neuronal synaptic function are known to be dependent upon the selective regulation of gene expression. In this paper, we will present evidence to show that chronic lithium exerts significant transcriptional and posttranscriptional effects, and that these actions of lithium may be mediated via protein kinase C (PKC)-induced alterations in nuclear transcription regulatory factors responsible for modulating the expression of proteins involved in long-term neural plasticity and cellular response. Such target sites for chronic lithium may help unravel the processes by which a simple monovalent cation can produce a long-term stabilization of mood in individuals vulnerable to bipolar illness.
Manji
H K
HK
Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, Maryland 20892.
Lenox
R H
RH
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008094:Lithium / Q000494:pharmacology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*
D007527:Isoenzymes; D008094:Lithium; D011493:Protein Kinase C