Human cellular differences in cAMP--CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder.
Eur J Neurosci
; 40(1): 2206-15, 2014 Jul.
Article
em En
| MEDLINE
| ID: mdl-24898566
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transtorno Bipolar
/
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico
/
AMP Cíclico
/
Luz
/
Melatonina
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Suíça