Figure 2.

CRF family of peptide hormones and their two G protein-coupled receptors (GPCR) receptors, CRF₁ and CRF₁. Based on in vitro binding assays, CRF binds mainly to CRF₁, whereas urocortin 1 (UCN1) binds to both receptors, but with 10-fold higher affinity than other ligands. UCN2 and UCN3 bind exclusively to CRF₂. The activation of CRF₁ receptors by CRF in the hypothalamus initiates the hypothalamic–pituitary–adrenal (HPA) axis, ultimately resulting in the release of glucocorticoids (cortisol in primates and corticosterone in rodents) from the adrenal cortex. Activation of CRF₂ by urocortins is key for recovery from stress responses and returning to homeostasis.