CRF Receptor

The neuropeptide corticotropin-releasing factor (CRF) and its relatives, the urocortins 1–3, in concert with their receptors (CRFR1, CRFR2), have emerged as central components of the physiological stress response. The CRFR1 and CRFR2 belong to the secretin-like family, also known as class B1, of G protein-coupled receptors (GPCRs). Several endogenous hormones mediate their responses through the CRF receptors, such as CRF and the urocortins. The structures for the N-terminus extracellular domain of both CRF1R and CRF2R in complex with peptidic ligands were released and permitted the study of hormone binding to the orthosteric binding site. Stimulation of CRFRs in cultures of primary pituitary cells leads to activation of Gs and elicits a cAMP response, most physiological functions of CRF/CRFR1 have been assigned to Gs coupling. 
CRFRs have the competence to couple to different G proteins, enabling them to activate a broad spectrum of downstream signaling pathways. CREB phosphorylation plays no role; instead the activation of PKA via CRF and cAMP stimulates two parallel signal transduction pathways. One signaling pathway is calcium dependent and involves the CaMKII. The other is calcium independent. In addition, CRF binding to CRFR1 activates the MAP kinase signaling pathway, which involves the small G proteins Rap1 and B-Raf, as well as the MAP kinases MEK and ERK1/2. This signal cascade leads to phosphorylation and activation of Nur77 (FIGURE 12). Ultimately, these different signaling pathways regulate the expression of POMC, from which ACTH is liberated by proteolytic processing.


1.Deussing JM,et al. Physiol Rev. 2018 Oct 1;98(4):2225-2286.