title: Human cellular differences in cAMP--CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder.
abstract: Various lines of evidence suggest a mechanistic role for altered cAMP-CREB (cAMP response element - binding protein) signaling in depressive and affective disorders. However, the establishment and validation of human inter-individual differences in this and other major signaling pathways has proven difficult. Here, we describe a novel lentiviral methodology to investigate signaling variation over long periods of time directly in human primary fibroblasts. On a cellular level, this method showed surprisingly large inter-individual differences in three major signaling pathways in human subjects that nevertheless correlated with cellular measures of genome-wide transcription and drug toxicity. We next validated this method by establishing a likely role for cAMP-mediated signaling in a human neuroendocrine response to light - the light-dependent suppression of the circadian hormone melatonin - that shows wide inter-individual differences of unknown origin in vivo. Finally, we show an overall greater magnitude of cellular CREB signaling in individuals with bipolar disorder, suggesting a possible role for this signaling pathway in susceptibility to mental disease. Overall, our results suggest that genetic differences in major signaling pathways can be reliably detected with sensitive viral-based reporter profiling, and that these differences can be conserved across tissues and be predictive of physiology and disease susceptibility.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 190 Winterthurerstrasse, Zurich, Switzerland.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Gaspar
authors.forename: Maan
authors.initials: M
authors.lastname: van de Werken
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Johansson
authors.forename: Ermanno
authors.initials: E
authors.lastname: Moriggi
authors.forename: Björn
authors.initials: B
authors.lastname: Owe-Larsson
authors.forename: Janwillem W H
authors.initials: JW
authors.lastname: Kocks
authors.forename: Gabriella B
authors.initials: GB
authors.lastname: Lundkvist
authors.forename: Marijke C M
authors.initials: MC
authors.lastname: Gordijn
authors.forename: Steven A
authors.initials: SA
authors.lastname: Brown
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000378:metabolism*; D002478:Cells, Cultured; D015331:Cohort Studies; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008027:Light; D008297:Male; D008550:Melatonin / Q000378:metabolism*; D008875:Middle Aged; D010775:Photic Stimulation; D015398:Signal Transduction; D044465:White People; D055815:Young Adult
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D000242:Cyclic AMP; D008550:Melatonin
keywords: bipolar disorder; cAMP-CREB; circadian; fibroblast; inter-individual differences; melatonin