cAMP-dependent protein kinase induces cAMP-response element-binding protein phosphorylation via an intracellular calcium release/ERK-dependent pathway in striatal neurons

Activation of the cAMP dependent protein kinase A (PKA) pathway may induce cAMP-response element-binding protein (CREB) phosphorylation either directl y or via cross-talk mechanisms with other signal transduction pathways. In this study, we have investigated in striatal primary cultures the mechanism by which activation of the cAMP/PKA-dependent pathway leads to CREB phosph orylation via the extracellular signal-regulated kinase (ERK) dependent pat hway. We have found that PKA-induced CREB phosphorylation and CREB-dependen t transcription are mediated by calcium (Ca2+) release from intracellular s tores and are blocked by inhibitors of the protein kinase C and ERK pathway s. This mechanism appears to be mediated by the small G-protein Rap1, whose activation appears to be primed by PKA-induced Ca2+ release but not furthe r induced by direct or indirect PKA- or protein kinase C-dependent phosphor ylation. These results suggest that, in striatal neurons, intracellular Ca2 + release, Rap1, and ERK pathway play a crucial role in the PKA induced CRE B phosphorylation and CREB-dependent transcription.