A novel molecular mechanism of corticotropin-releasing factor action in neurons
Senior Associate Consultant, L.E.K. Consulting
Undergraduate Institution and Major/Degree:
Saint Vincent College, BS, Biochemistry, 2006
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. My thesis work has focussed on elucidating the intracellular signaling pathways by which stress peptides influence both striatal and hippocampal neurons. We have identified a novel intracellular signaling pat!
hway 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 stress-peptide sensitive tissues.
- Paul Mermelstein
- Paulo Kofuji
- Mark Thomas
Courses Taken Beyond the Core Courses:
- BioC 4332 Biochemistry II
- PubH 6450 Biostatistics I
- Nsc 5667 Neurobiology of Disease
- PHCL 5462 Neuroscience Principles of Drug Abuse
Graduate Level Minor:
- Supporting program
- Society for Neuroscience Annual Meeting 2006, 2007, 2008, 2010
- Steroid Hormones and Brain Function 2008
- William Engeland - Chair
- Paul Mermelstein - Advisor
- Lorene Lanier
- Mark Thomas
- Bob Meisel
- Luoma JI, Stern CM, and Mermelstein PG (2011) Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection. The Journal of Steroid Biochemistry and Molecular Biology, Epub ahead of print.
- Stern CM, Meitzen J, and Mermelstein PG (2011) Corticotropin-releasing factor and urocortin I activate CREB through functionally selective Gβγ signaling in hippocampal pyramidal neurons. European Journal of Neuroscience 34(5): 671-681.
- Stern CM, Luoma JI, Meitzen J, and Mermelstein PG (2011) Corticotropin releasing factor-induced CREB activation in striatal neurons occurs via a novel Gβγ signaling pathway. PLoS One 6(3): e18114.
- Stern CM (2011) Corticotropin-releasing factor in the hippocampus: eustress or distress? Journal of Neuroscience 31(6): 1935 - 1936.
- Meitzen J, Luoma JI, Stern CM, and Mermelstein PG (2011) b1-adrenergic receptors activate two distinct signaling pathways in striatal neurons. Journal of Neurochemistry 116(6): 984 - 995.
- Meitzen J, Pflepsen KR, Stern CM, Meisel RL, and Mermelstein PG (2011) Measurements of neuron size and density in rat dorsal striatum, nucleus accumbens core and shell: differences between striatal region and brain hemisphere, but not sex. Neuroscience Letters 487(2): 177-181.
- Stern CM and Mermelstein PG (2010) Caveolin regulation of neuronal intracellular signaling. Cellular and Molecular Life Sciences 67(22): 3785-3795.
- Society for Neuroscience, 2006-Present
- New Castle, PA