Novel calcitonin-(8–32)-sensitive adrenomedullin receptors derived from co-expression of calcitonin receptor with receptor activity-modifying proteins

Abstract

We tested whether heterodimers comprised of calcitonin (CT) receptor lacking the 16-amino acid insert in intracellular domain 1 (CTR I1−) and receptor activity-modifying protein (RAMP) can function not only as calcitonin gene-related peptide (CGRP) receptors but also as adrenomedullin (AM) receptors. Whether transfected alone or together with RAMP, human (h)CTR I1− appeared mainly at the surface of HEK-293 cells. Expression of CTR I1− alone led to significant increases in cAMP in response to hCGRP or hAM, though both peptides remained about 100-fold less potent than hCT. However, the apparent potency of AM, like that of CGRP, approached that of CT when CTR I1− was co-expressed with RAMP. CGRP- or AM-evoked cAMP production was strongly inhibited by salmon CT-(8–32), a selective amylin receptor antagonist, but not by hCGRP-(8–37) or hAM-(22–52), antagonists of CGRP and AM receptors, respectively. Moreover, the inhibitory effects of CT-(8–32) were much stronger in cells co-expressing CTR I1− and RAMP than in cells expressing CTR I1− alone. Co-expression of CTR I1− with RAMP thus appears to produce functional CT-(8–32)-sensitive AM receptors.