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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28
Fiscal Year
2014
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U.S. National Institute of Mental Health
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Eiden, Lee E; Emery, Andrew C; Zhang, Limei et al. (2018) PACAP signaling in stress: insights from the chromaffin cell. Pflugers Arch 470:79-88
Zhang, Limei; Hernández, Vito S; Swinny, Jerome D et al. (2018) A GABAergic cell type in the lateral habenula links hypothalamic homeostatic and midbrain motivation circuits with sex steroid signaling. Transl Psychiatry 8:50
Jiang, Sunny Zhihong; Xu, Wenqin; Emery, Andrew C et al. (2017) NCS-Rapgef2, the Protein Product of the Neuronal Rapgef2 Gene, Is a Specific Activator of D1 Dopamine Receptor-Dependent ERK Phosphorylation in Mouse Brain. eNeuro 4:
Emery, Andrew C; Xu, Wenqin; Eiden, Maribeth V et al. (2017) Guanine nucleotide exchange factor Epac2-dependent activation of the GTP-binding protein Rap2A mediates cAMP-dependent growth arrest in neuroendocrine cells. J Biol Chem 292:12220-12231
Wollam, Joshua; Mahata, Sumana; Riopel, Matthew et al. (2017) Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion. Cell Tissue Res 368:487-501
Emery, Andrew C; Alvarez, Ryan A; Eiden, Maribeth V et al. (2017) Differential Pharmacophore Definition of the cAMP Binding Sites of Neuritogenic cAMP Sensor-Rapgef2, Protein Kinase A, and Exchange Protein Activated by cAMP in Neuroendocrine Cells Using an Adenine-Based Scaffold. ACS Chem Neurosci 8:1500-1509
Jiang, Sunny Zhihong; Eiden, Lee E (2016) Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse. Stress 19:374-82
Emery, Andrew C; Alvarez, Ryan A; Abboud, Philip et al. (2016) C-terminal amidation of PACAP-38 and PACAP-27 is dispensable for biological activity at the PAC1 receptor. Peptides 79:39-48
Pasqua, Teresa; Mahata, Sumana; Bandyopadhyay, Gautam K et al. (2016) Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo. Cell Tissue Res 363:693-712
Wächter, Christian; Eiden, Lee E; Naumann, Nedye et al. (2016) Loss of cerebellar neurons in the progression of lentiviral disease: effects of CNS-permeant antiretroviral therapy. J Neuroinflammation 13:272

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