FIGURE 1.

Signaling cascade of CREB. Adenylate cyclase (AC) activated upon stimulation of cellular G-protein-coupled receptors (GPCR) by neurotransmitters increases cAMP levels, which, in turn, activate PKA. The catalytic subunits of PKA translocate into the nucleus and phosphorylate CREB at Ser133. Binding of growth factors to receptor tyrosine kinases (RTK) stimulate the activation of PI3K/Akt/GSK3β, Ras/Raf/MEK/ERK/p90/RSK and ERK/MSK1 signaling pathways, which subsequently enhance the phosphorylation of CREB at different sites. Additionally, activation of excitatory NMDA receptors will increase the phosphorylation of CREB through Ca²⁺/CaMK-dependent pathways.