A novel molecular mechanism of stress peptide action in neurons.

Stern, Christopher Michael
2010-12
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A novel molecular mechanism of stress peptide action in neurons.

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2010-12

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Stress is any actual or perceived disturbance of an organism’s environment. The acute response to stress includes the release of corticotropin-releasing factor (CRF) from the hypothalamus to activate the pituitary and downstream glucocorticoid secretion. In addition to this classical role, CRF also influences many extra-hypothalamic brain regions including the striatum and the hippocampus. CRF and the related stress peptide Urocortin 1 (UCN) exert their cellular effects by binding to one of two cognate G-protein coupled receptors (GPCRs), CRF receptor 1 (CRFR1) or 2 (CRFR2). While these GPCRs were initially characterized as being coupled to adenylyl cyclase, cAMP and PKA signaling, it has since become clear that CRFRs couple to numerous intracellular signaling cascades. Here, I describe work elucidating the intracellular signaling pathways by which stress peptides influence both striatal and hippocampal neurons. This document describes a novel intracellular signaling pathway whereby CRF and UCN lead to a rapid Gβγ-dependent increase in phosphorylation of the activity-dependent transcription factor CREB. These data not only describe a completely original mechanism of stress peptide signaling in neurons, but also include the first direct demonstrations of Gβγ-mediated CREB phosphorylation in any cellular system. Together, these results suggest that stress peptide influence of Gβγ signaling may be a fundamental, yet underexplored, molecular mechanism by which stress influences both the central nervous system and other stresspeptide sensitive tissues.

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University of Minnesota Ph.D. dissertation. December 2010. Major: Neuroscience. Advisor: Paul Gary Mermelstein, Ph.D. 1 computer file (PDF): vii, 77 pages. Ill. (some col.)

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Stern, Christopher Michael. (2010). A novel molecular mechanism of stress peptide action in neurons.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/101004.

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