Mechanisms of vinpocetine action. (A) Adenylyl cyclase activity increases cAMP levels, activating PKA. Active forms of PKA may translocate to the nucleus and phosphorylate CREB. Similarly, guanylyl cyclase activity increases cGMP levels, activating the Ras/Raf pathway either directly or through PKG. This leads to the activation of ERK and the phosphorylation of both CREB and SRF. Because PDE1 catalyzes the hydrolysis of cAMP and cGMP, its inhibition by vinpocetine increases the level of these cyclic nucleotides, ultimately leading to the expression of plasticity-related genes. (B) In its inactive state, NFκB is located in the cytoplasm attached to its inhibitory subunit IκB. Inflammatory signals activate the IKK complex, which in turn phosphorylates IκB. IκB phosphorylation leads to its ubiquitination (and eventual degradation) by ubiquitin enzymes (UE). Without IκB, NFκB translocates to the nucleus, where it phosphorylates κB sites in many genes, which results in the expression of many proinflammatory molecules. Vinpocetine blocks IKK activity, preventing NFκB-triggered protein expression.