Corticotropin-releasing hormone (CRH) is the principal regulator of the 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 been observed involving the immune and cardiovascular systems. Specific CRH binding studies in several peripheral organs, as well as functional studies, have implied the existence of peripheral CRH receptors. Although 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 murine CRH receptor that is highly expressed in the heart. The newly cloned CRH receptor cDNA (CRH-R2) was isolated from a mouse heart cDNA library and encodes a 430-amino acid protein containing seven putative transmembrane domains characteristic of G protein-coupled receptors. CRH-R2 is 69% identical with the previously identified murine pituitary CRH receptor and is encoded by a distinct gene. In addition to a high level of expression in the heart, weak expression was also observed in the brain and lungs. Functional studies using CRH-R2-transfected cells indicate that CRH and the CRH-related amphibian peptide, sauvagine, bind with high affinity to CRH-R2 and stimulate intracellular accumulation of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)