The biological effects of CRH are mediated by at least two different receptors, CRH-R1 and CRH-R2 that belong to the G-protein coupled receptor superfamily and typically are positively coupled to adenylate cyclase (29, 30). The affinity that CRH exhibits towards CRH-R1 is ten times higher than towards CRH-R2 (29). These two receptors are products of separate genes. CRH-R1 is encoded by human chromosome 17q21 while CRH-R2 is encoded by human chromosome 7p14 (31, 32). For CRH-R1 there have been identified alternatively spliced isoforms a, b, c, and d, whereas isoforms a, b, c plus a stomach variant have been identified for CRH-R2 (33). The CRH-R subtypes share a 70% homology of their amino acid sequence but exhibit unique pharmacologic profiles. They are differentially expressed and appear to mediate selective actions of CRH at different tissues. CRH-R1 expression is highest in the cerebral cortex, striatum, amygdale and cerebellum. On the other hand, CRH-R2 is mostly present in subcortical structures such as the lateral septal nucleus, several nuclei of the hypothalamus and the choroid plexus (34). At the periphery, CRH-R2 is widely expressed in the gastrointestinal tract, the lung, skeletal muscle, arteries and the heart muscle. Indeed, peripherally injected CRH augments gastrointestinal motility, inhibits gastric secretion, lowers blood pressure and affects heart output and decreases inflammatory reactions. The two receptors are probably involved in some coordinate ways to express the totality of the physiological responses to stress including behavioral responses (28). CRH-R1 alpha is present on both epithelial and stromal cells of the human endometrium (35).

In the anterior pituitary, CRH binds to CRH-R1 of the corticotrophs (36). The ACTH response can be modulated by the number of CRH-R in these cells. Immobilization, stress, adrenalectomy, administration of CRH, AVP or glucocorticoids, reduces the number of CRH-R in the anterior pituitary but not in the brain (37). Binding of CRH to the receptor results in adenylcyclase activation, leading to an increase in intracellular cAMP concentration. The coupling of CRH receptor and G protein may also stimulate other cAMP pathway events in a variety of brain-derived and peripheral cell lines. These events include the cross-talk between CRH receptor-initiated signal transduction and activation of NF-kB in T cell. The molecular mechanism of this effect has recently been established through experiments using cultures of mouse thymocytes (38). It was shown that the CRH-induced activation of the nuclear factor-κ B was mediated by two protein kinase systems, Protein Kinase A (PKA) and Protein Kinase C (PKC) (39, 40).