The neuropeptide slow transmitter PACAP (pituitary adenylate cyclase activating polypeptide) is released at synapses that transduce stress responses to the brain, and mediate homeostatic adjustments to stress by the organism. Allostatic responses to systemic and psychogenic stressors at multiple points in development and throughout the life span are implicated as causative factors in depression and post-traumatic stress disorder (PTSD). Stress response pathways (resilience responses) may also be required to ameliorate delayed neuronal death (DND) in traumatic brain injury, long-term exposure to intense physical or psychological stimuli, or brain inflammation in chronic neurodegenerative disease. Understanding the cellular mechanisms of stress transduction is crucial to developing effective therapeutic interventions for these disorders. In completing the first part of our long-term goal to identify the specific contributions of the three major cAMP sensors PKA, Epac (Rapgef2 3 and 4), and NCS/Rapgef2 to major cAMP-dependent processes carried out by neuronal cells, we have demonstrated in the NS-1 neuroendocrine cell line that PKA (and not Epac or NCS/Rapgef2) is required for cAMP-dependent cell survival upon serum withdrawal;that Epac (and not PKA or NCS/Rapgef2) is required for cAMP-dependent growth arrest;and that NCS/Rapgef2 (and not PKA or Epac) is required for cAMP-initiated neuritogenesis (A.C. Emery, M.V. Eiden and L.E. Eiden, J.Biol. Chem. 289: 10126, 2014). Further efforts are underway to show that the concept of parcellation of these three cAMP pathways also applies to neurons and neuronal progenitor cells of the central nervous system. Progress towards completion of our second major goal of demonstrating a physiological role for the cAMP-NCS/Rapgef2-ERK signaling cassette in the central nervous system has involved, as a first step, an inventory of the Gs-coupled GPCRs capable of signaling through this pathway. At this writing, five GPCRs tested appear to signal through engagement of NCS/Rapgef2, while two do not, indicating that cAMP-NCS/Rapgef2-ERK signaling is likely to be a property of most, but not all, Gs-coupled GPCRs.
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