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. Having in the previous year identified 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 NS-1 neuroendocrine cells and primary neurons in cellula (A.C. Emery, M.V. Eiden and L.E. Eiden, J.Biol. Chem. 289: 10126, 2014), we have now begun efforts to determine the relative contributions of the three sensors to cAMP-dependent effects mediated by the Gs-coupled PACAP receptor PAC1 and the dopamine receptor D1, in the extended amygdala and in the ventral striatum, respectively, during the processes of development of chronic stress-induced depressive behavior, and psychomotor stimulant-induced plasticity of medium spiny neurons, respectively.

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Support Year
29
Fiscal Year
2015
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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
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Pasqua, Teresa; Mahata, Sumana; Bandyopadhyay, Gautam K et al. (2016) Erratum to: Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo. Cell Tissue Res 363:823
Jenkins, Danielle E; Sreenivasan, Dharshini; Carman, Fiona et al. (2016) Interleukin-6-mediated signaling in adrenal medullary chromaffin cells. J Neurochem 139:1138-1150
Hernández, Vito S; Hernández, Oscar R; Perez de la Mora, Miguel et al. (2016) Hypothalamic Vasopressinergic Projections Innervate Central Amygdala GABAergic Neurons: Implications for Anxiety and Stress Coping. Front Neural Circuits 10:92

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