Lithium salts are clinically important drugs used to treat bipolar mood disorder. The mechanisms accounting for the clinical efficacy are not completely understood. Chronic treatment with lithium is required to establish mood stabilization, suggesting the involvement of neuronal plasticity processes. CREB (cAMP-response-element-binding protein) is a transcription factor known to mediate neuronal adaptation. Recently, the CREB-co-activator TORC (transducer of regulated CREB) has been identified as a novel target of lithium and shown to confer an enhancement of cAMP-induced CREB-directed gene transcription by lithium. TORC is sequestered in the cytoplasm and its nuclear translocation controls CREB activity. In the present study, the effect of lithium on TORC function was investigated. Lithium affected neither the nuclear translocation of TORC nor TORC1 transcriptional activity, but increased the promoter occupancy by TORC1 as revealed by chromatin immunoprecipitation assay. In a mammalian two-hybrid assay, as well as in a cell-free GST (glutathione transferase) pull-down assay, lithium enhanced the CREB–TORC1 interaction. Magnesium ions strongly inhibited the interaction between GST–CREB and TORC1 and this effect was reversed by lithium. Thus our results suggest that, once TORC has entered the nucleus, lithium as a cation stimulates directly the binding of TORC to CREB, leading to an increase in cAMP-induced CREB target-gene transcription. This novel mechanism of lithium action is likely to contribute to the clinical mood-stabilizing effect of lithium salts.

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