A calcitonin receptor complementary DNA (cDNA) was cloned by expression of a cDNA library from a porcine kidney epithelial cell line in COS cells. The 482-amino acid receptor has high affinity for salmon calcitonin (dissociation constant Kd approximately 6 nM) and is functionally coupled to increases in intracellular cyclic adenosine monophosphate (cAMP). The receptor shows no sequence similarity to other reported G protein-coupled receptors but is homologous to the parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor, indicating that the receptors for these hormones, which regulate calcium homeostasis, represent a new family of G protein-coupled receptors.