Corticotropin-releasing factor and urocortin I activate CREB through functionally selective Gβγ signaling in...

Stress is a perceived perturbation in the environment of the organism that affects numerous extrahypothalamic brain regions including the hippocampus, a limbic structure critical for learning, spatial memory and the regulation of stress hormones. Though many effects of stress on the hippocampus are mediated via local glucocorticoid action, there is now ample evidence for the contributions of the stress peptides corticotropin-releasing factor (CRF) and urocortin I (UCN). Thus, understanding the intracellular signaling pathways activated by stress peptides is required to fully understand the mechanisms by which stress influences the hippocampus. Here we elucidate molecular mechanisms by which CRF and UCN induce phosphorylation of the activity-dependent transcription factor CREB, a molecule critical for numerous forms of neuronal plasticity. We report that nanomolar concentrations of both CRF and UCN lead to a rapid, CRF receptor 1 (CRFR1)- and Gβγ-dependent increase in CREB phosphorylation in rat hippocampal pyramidal neurons. Interestingly, CRF- and UCN-induced signaling pathways diverge downstream of Gβγ, with UCN, but not CRF, signaling to CREB via a MEK/MAPK-dependent pathway. These data suggest novel molecular mechanisms by which stress can directly impact hippocampal neurons, as well as highlight an emerging role for Gβγ signaling in mediating the effects of stress peptides in extrahypothalamic stress-responsive brain regions.