Fig. 2.

Neurotrophins, the ERK MAP kinase signaling cascade, and GSK-3. Cell survival is dependent on neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor, and the expression of these factors can be induced by synaptic activity. The influence of neurotrophic factors on cell survival is mediated by activation of the MAP kinase cascade. Activation of neurotrophic factor receptors also referred to as Trks, results in activation of the MAP kinase cascade via several intermediate steps, including phosphorylation of the adaptor protein SHC and recruitment of the guanine nucleotide exchange factor Sos. This results in activation of the small guanosine triphosphate-binding protein Ras, which leads to activation of a cascade of serine/threonine kinases. This includes Raf, MAP kinase kinase (MEK), and MAP kinase (also referred to as extracellular response kinase, or ERK). One target of the MAP kinase cascade is RSK, which influences cell survival in at least two ways. RSK phosphorylates and inactivates the pro-apoptotic factor BAD. RSK also phosphorylates CREB and thereby increases the expression of the anti-apoptotic factor bcl-2 and BDNF. These mechanisms underlie many of the long-term effects of neurotrophins, including neurite outgrowth, cytoskeletal remodeling, and cell survival. Recent evidence suggests that lithium and VPA activate the ERK MAP kinase pathway. Lithium and VPA also appear to target GSK-3 and the Wnt signaling pathway. The function of GSK-3 in the Wnt signaling pathway – whereby Wnt glycoproteins interact with the frizzled family of receptors to stimulate the disheveled-mediated inactivation of GSK-3 and activation of the transcription factor β-catenin – is separate from the PI₃ kinase/AKT mediated inactivation of GSK-3. Lithium is a direct inhibitor of GSK-3; both lithium and VPA increase β-catenin levels.