Role of the ERK/MSK1 signalling pathway in chromatin remodelling and brain responses to drugs of abuse.

摘要

Drugs of abuse induce neuroadaptations through regulation of gene expression. Although much attention has focused on transcription factor activities, new concepts have recently emerged on the role of chromatin remodelling as a prerequisite for regulation of gene expression in neurons. Thus, for transcription to occur, chromatin must be decondensed, a dynamic process that depends on post-translational modifications of histones. We review here these modifications with a particular emphasis on the role of histone H3 phosphorylation at the promoter of specific genes, including c-fos and c-jun. We trace the signalling pathways involved in H3 phosphorylation and provide evidence for a role of mitogen and stress-activated protein kinase-1 (MSK1) downstream from the MAPK/extracellular-signal regulated kinase (ERK) cascade. In response to cocaine, MSK1 controls an early phase of histone H3 phosphorylation at the c-fos promoter in striatal neurons. MSK1 action may be potentiated by the concomitant inhibition of protein phosphatase 1 by nuclear translocation of dopamine- and cAMP-regulated phosphoprotein Mr = 32 000. H3 phosphorylation by MSK1 is critically involved in c-fos transcription, and cocaine-induced locomotor sensitization. Thus, ERK plays a dual role in gene regulation and drug addiction by direct activation of transcription factors and by chromatin remodelling.