CRH is produced in the parvocellular division of the PVN and released into the hypophysial portal circulation to stimulate ACTH synthesis and secretion, thus playing a critical role in the HPA axis regulation. The activity of CRH neurons is regulated by humoral factors such as glucocorticoid and IL-1 as well as numerous kinds of neural inputs within and from outside of the hypothalamus. Circulating glucocorticoids readily have access to the CRH neurons and thereby exert a potent inhibitory action on CRH gene transcription. The molecular mechanisms involved in the glucocorticoid negative feedback remain to be fully understood. IL-1, produced in the periphery during the inflammatory process, is a potent stimulatory factor for CRH neurons. It is not yet clear how a protein of this large molecular weight has access to brain tissues through the blood brain barrier, nor is it clear through which neural pathway the IL-1-mediated signal is conveyed to the hypothalamus.
A number of neurotransmitter/modulator candidates have been implicated in the regulation of CRH neurons. Functional roles and anatomical pathways have been explored by pharmacological methods, ablation of specific neural pathway(s), and the neural tracingethod. Despite the substantial knowledge produced by these studies, physiological and/or pathophysiological roles of the respective neural circuitry are still obscure.
Two major intracellular signal transduction systems, the CAMP-dependent PKA pathway and diacylglycerol-dependent PKC pathway, are implicated in transcriptional regulation of the CRH gene. The functionality of the CRE, 5'-flanking the CRH gene, has been well established in cell culture system transfected with CRH promoter-reporter constructs, thus the cAMP-dependent PKA pathway may play an essential role in CRH gene expression. The role of the PKC pathway is still controversial and requires further exploration.