The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus

Activation of the mitogen-activated protein kinase (MAPK) cascade recently was discovered to play an important role in synaptic plasticity in area CA1 of rat hippocampus. However, the upstream mechanisms regulating MAPK activ ity and the downstream effecters of MAPK in the hippocampus are uncharacter ized. In the present studies we observed that hippocampal MAPK activation i s regulated by both the PKA and PKC systems; moreover, we found that a wide variety of neuromodulatory neurotransmitter receptors (metabotropic glutam ate receptors, muscarinio acetylcholine receptors, dopamine receptors, and beta-adrenergic receptors) couple to MAPK activation via these two cascades . In additional studies we observed that PKC is a powerful regulator of CRE B phosphorylation in area CA1. MAPK plays a critical role in transcriptiona l regulation by PKC, because MAPK activation is a necessary component for i ncreased CREB phosphorylation in response to the activation of this kinase. Surprisingly, we also observed that MAPK activation is necessary for PKA c oupling to CREB phosphorylation in area CA1. Overall, these studies indicat e an unexpected richness of diversity in the regulation of MAPK in the hipp ocampus and suggest the possibility of a broad role for the MAPK cascade in regulating gene expression in long-term forms of hippocampal synaptic plas ticity.