The individual signaling cascades that activate ERK, PKA, PKC, CaMKII, and Fyn often affect each other, resulting in cross-talk that can influence the activity or downstream effects of other kinases. These interactions can have similar or opposing effects on downstream targets. PKA and ERK signaling pathways converge, resulting in phosphorylation of the same serine residue on CREB. PKA can also indirectly activate ERK by activating the small G-protein Rap1, which then activates B-Raf, leading to activation of MEK and ERK (Fig. 1).60 Thus, PKA cross-talk with ERK can amplify CREB-mediated gene transcription. CaMKII indirectly modulates the stimulantinduced activation of PKA and ERK signaling pathways. CaMKII inhibitors decrease the activation of ERK by nicotine,37 decrease the activation of ERK and CREB by amphetamine,236 and decrease D175 and NMDA agonist induction of CREB.240 Thus, the inhibition of CaMKII activity may have negative effects on the downstream targets of PKA and ERK pathways.
