Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Smad proteins are intracellular transducers for transforming growth factor-β (TGF-β) signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-β and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3β protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP–protein kinase A (PKA), AKT–glycogen synthase kinase-3β (GSK-3β), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREBSer133 protein levels, an enhanced interaction between pCREBSer133 and p300/CBP, which causes Smad3/4–p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.