CRF is largely a CRF1R agonist and displays 18-fold greater affinity for CRF1R than CRF2R (Vaughan et al., 1995). In contrast, urocortins are high-affinity agonists for CRF2R, with varying degrees of affinity for CRF1R: Ucn1 binds both receptor subtypes with high affinity, and Ucn1 positive fibers innervate regions expressing both receptors. Ucn2 and 3 are highly CRF2R selective (Bittencourt et al., 1999; Fekete and Zorrilla, 2007). The urocortins also have varying affinity for the CRF binding protein (CRFBP): Ucn1 binds to the CRFBP, while Ucn3 does not, and the affinity of Ucn2 for CRFBP is species-dependent (Fekete and Zorrilla, 2007). Though early findings showed that CRFBP inhibits CRF/CRF1R signaling (Potter et al., 1991), more recent data suggest that interactions with CRFBP may be required for some actions of CRF/Ucn at the CRF2R (Ungless et al., 2003; Wang et al., 2007).
