Actions of CRF and its analogs

Corticotropin-releasing factor (CRF), urocortin, sauvagine and urotensin 1 form the CRF family. These peptides bind with different affinities to two s ubtypes of CRF receptor (CRFR), CRFR1 and CRFR2. The latter exists as two s plice variants, the neuronal CRFR2 alpha and the peripheral CRFR2 beta. CRF R is a G protein-dependent receptor which acts mainly through G(s) enhancin g cAMP production. However, CRFR1 expressed in neutrophils of the spleen in response to immunologic stimulation and psychological stress does not seem to function through G(s) as indicated by the inability of CRF to stimulate the cAMP production of CRFR1(+) neutrophils. Besides the two receptors, a 37 kD CRF binding protein (CRF-BP) binds several CRF peptides with high aff inity. CRFR and CRF-BP do not share a common amino acid sequence representi ng the ligand binding site. In view of the unusually slow off rate of CRF-B P, it is proposed that CRF-BP provides an efficient uptake of free extracel lular CRF. Thus, the time of exposure of CRFR to GRF or urocortin can be li mited. At this time, the fate of the ligand CRF-BP complex is unclear. CRFR 1 is not only involved in the hypophyseal stimulation of corticotropin rele ase, but hippocampal CRFR1 mediates enhancement of stress-induced learning. CRFR1 may also be involved in basic anxiety. In contrast, at least in the mouse, CRFR2 of the lateral intermediate septum mediates tonic impairment o f learning. In response to stressful stimuli or after local injection of hi gh CRF doses, CRFR2 mediates anxiety. Effects requiring CRFR2 can be blocke d specifically by the recently developed peptidic antagonist antisauvagine- 30.