A novel molecular mechanism of stress peptide action in neurons.

Abstract

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.