Calcitonin gene-related peptide (CGRP) receptors (CGRP-Rs) are widely distributed throughout the central and peripheral nervous systems. A novel CGRP-R was identified from a porcine lung complementary DNA library. Sequence analysis indicated that the CGRP-R is 462 amino acids in length and shares 93% sequence identity with the human CGRP-R. Northern blot analysis indicated a messenger RNA species of 5.4 kilobases, which is abundantly expressed in the lung. Ligand binding studies of the cloned CGRP-R expressed in human embryonic kidney (HEK-293) cells showed the presence of high affinity receptor for CGRP with a Kd of 38.5 pM. The pharmacological profiles of various ligands competing for [125I]CGRP binding to the expressed receptor were in accordance with those for the natural receptor. Binding of [125I]CGRP to the expressed receptor was decreased in the presence of a nonhydrolyzable analog of GTP, guanosine 5' (gamma-thio)-triphosphate. In functional studies, CGRP stimulated the activation of adenylyl cyclase with an EC50 of 2.5 nM. The linear analog of CGRP, diacetoamidomethyl cysteine CGRP, did not affect adenylyl cyclase activity on its own or in the presence of CGRP. Furthermore, the CGRP receptor antagonists, CGRP-(8-37)alpha, inhibited the CGRP-mediated response in a competitive manner. Collectively, the binding and functional data demonstrate that we have cloned a porcine CGRP type 1 receptor. The availability of the CGRP-R complementary DNA will allow us to examine its participation in pathophysiological processes.