IDENTIFICATION OF A NOVEL MURINE RECEPTOR FOR CORTICOTROPIN-RELEASINGHORMONE EXPRESSED IN THE HEART

Corticotropin-releasing hormone (CRH) is the principal regulator of th e stress response. CRH stimulates production of ACTH via specific CRH receptors located on pituitary corticotropes. In addition to pituitary and central nervous system effects, peripheral effects of CRH have be en observed involving the immune and cardiovascular systems. Specific CRH binding studies in several peripheral organs, as well as functiona l studies, have implied the existence of peripheral CRH receptors. Alt hough a pituitary/brain CRH receptor has recently been identified, it is expressed at very low levels in peripheral sites where CRH effects have been observed. We report here the identification of a novel murin e CRH receptor that is highly expressed in the heart. The newly cloned CRH receptor cDNA (CRH-R2) was isolated from a mouse heart cDNA libra ry and encodes a 430-amino acid protein containing seven putative tran smembrane domains characteristic of G protein-coupled receptors. CRH-R P is 69% identical with the previously identified murine pituitary CRH receptor and is encoded by a distinct gene. In addition to a high lev el of expression in the heart, weak expression was also observed in th e brain and lungs. Functional studies using CRH-RP-transfected cells i ndicate that CRH and the CRH-related amphibian peptide, sauvagine, bin d with high affinity to CRH-RP and stimulate intracellular accumulatio n of cAMP. Interestingly, sauvagine bound CRH-RP at an affinity SO-fol d higher than CRH, an important finding in light of sauvagine's greate r potency in mediating hypotensive effects in the peripheral vascular system. Thus, this new receptor represents the first CRH receptor expr essed at high levels in the periphery and may mediate the effects of C RH in cardiac function and the response to stress.