Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Cr
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Daniela Tardito, Jorge Perez, Ettore Tir
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参见附件。
Center of Neuropharmacology, Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milan, Italy (D.T., E.T., L.M., G.R., M.P.)
Biological Psychiatry Unit, Istituto di Ricovero e Cura a Carattere Scientifico Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy (J.P., G.R.)
Abstract
Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and possible directions for future research. Particularemphasis is given to the regulation of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, which has been implicated in both the pathophysiology and pharmacology of mood disorders. The array of different results obtained by various groups is analyzed with an eye on recent advancements in the regulation of BDNF transcription, in an attempt to understand better the mechanisms of drug action and dissect molecular requirements for faster and more efficient antidepressant treatment.
I. Introduction: Regulation of Gene Expression and Neuroplasticity
Activity-dependent regulation of gene expression represents a general mechanism whereby neurons and neuronal networks adapt their short- and long-term responses to environmental stimuli. Several families of proteins, called transcription factors, carry out this function by binding to specific domains in the promoter region of various genes and by stimulating mRNA transcription (Kandel, 2001; Lonze and Ginty, 2002; West et al., 2002). A limited number of genes, estimated to be in the range of 15 to 300, show activity-dependent up-regulation in the nervous system, whereas the number of genes down-regulated is much lower, suggesting that gene induction is the favored process for long-term neuronal adaptations (West et al., 2002). A large number of transcription factors that regulate a wide variety of physiological processes have been identified; among them cAMP-response element binding protein (CREB1), a member of a family of transcription factors including CREB, cAMP-responsive element modulator, and activating transcription factor 1, stands out as the most widely expressed and most thoroughly investigated so far ......
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