Diverse roles of Corticotropin Releasing Factor Receptors and their Ligands
The Salk Institute for Biological Studies
La Jolla, CA
Corticotropin releasing factor, CRF, plays a major role in homeostasis by
mediating the endocrine, autonomic, immune and behavioral responses to
stress. The actions of CRF result from activation of its receptors, CRF-R1 and
CRF-R2, which are encoded by distinct genes and belong to the family of
7-TMD receptors which includes those for GRF, secretin, calcitonin and PTH.
The receptors couple to GTP-binding proteins and activate adenylate cyclase.
CRF-R1 is widely expressed in the central nervous system and also in the
pituitary, gonads, thymus and adrenals. One splice variant of CRF-R2 is
expressed mainly in the central nervous system while the other variant is
appears in the heart, skeletal muscle, epididymis and GI tract. The second
mammalian CRF-related peptide, urocortin, Ucn is found in many brain areas
and also in the heart, GI tract and immune system, regions of high expression
of CRF-R2. Pharmacology of the CRF ligand family, including (fish) urotensin,
(frog) sauvagine and (insect) diuretic hormone show that all the CRF ligands
bind with similar high affinity to CRF-R1, but urocortin, urotensin and sauvagine
are more potent than CRF for CRF-R2. Ucn is a potent anti-inflammatory
agent, modulates vascular tone, displays cardiovascular effects, and acting
centrally, reduces appetite and food intake. Transgenic mice lacking functional
CRF-R1 display impaired stress responses, reduced anxiety and lack of acute
anorectic effect of Ucn. In contrast, CRF-R2 knock-out mice show
hypersensitivity to stress, anxiety-like behavior, reduced food intake following
food deprivation and lack of Ucn-induced hypotension. The future holds
promise for discovering new CRF ligands and receptors and further
understanding of their manifold physiologic roles.