Molecular Regulation of Corticotropin-Releasing Hormone Gene Expression in Parvocellular Neurons of the Hypothalamic Paraventricular Nucleus

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  • AGUILERA Greti
    Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health

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Adequate regulation of corticotropin releasing hormone (CRH) secretion and expression is essential for endocrine, autonomic and behavioral stress adaptation. Maintenance of messenger RNA levels for peptide synthesis requires rapid but limited activation of CRH gene transcription. Activation of CRH transcription depends on cyclic AMP/protein kinase A signaling and binding of phospho-CREB to a critical cyclic AMP response element (CRE) at -270 in the CRH promoter. DNA methylation of the CRE CpG reduces CREB binding to the promoter affecting CRH expression. CREB-dependent activation of CRH transcription requires recruitment of the CREB co-activator, Transducer Of Regulated CREB activity (TORC). Cyclic AMP activates TORC by inhibiting salt induced kinase (SIK) type 2 allowing TORC dephosphorylation and nuclear translocation. Termination of the transcriptional response is essential for preventing pathology associated with chronic elevations of CRH and HPA axis activity. Glucocorticoid feedback inhibition, mainly through modulation of afferent pathways to hypothalamic CRH neurons, plays an important role. In addition, intracellular feedback mechanisms involving, Inducible Cyclic AMP Early Repressor (ICER), and cAMP-induced SIK1 activation and consecutive TORC inactivation, contribute to limiting CRH transcription. Understanding the molecular mechanisms of regulation of CRH expression is essential for understanding the pathogenesis and developing new therapeutic approaches for stress related disorders.

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