The pharmacology of adrenomedullin receptors and their relationship to CGRP receptors

Adrenomedullin (AM) has two specific receptors formed by the calcitonin-receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3. These are known as AM(1) and AM(2) receptors, respectively. In addition, AM has appreciable affinity for the CGRP(1) receptor, composed of CL and RAMP1. The AM(1) receptor has a high degree of selectivity for AM over CGRP and other peptides, and AM(22-52) is an effective antagonist at this receptor. By contrast, the AM2 receptor shows less specificity for AM, having appreciable affinity for betaCGRP Here, CGRP(8-37) is either equipotent or more effective as an antagonist than AM(22-52), depending on the species from which the receptor components are derived. Thus, under the appropriate circumstances it seems that betaCGRP might be able to activate both CGRP(1) and AM(2) receptors and AM could activate both AM(1) and AM(2) receptors as well as CGRP, receptors. Current peptide antagonists are not sufficiently selective to discriminate between these three receptors. The CGRP-selectivity of RAMP1 and RAMP3 may be conferred by a putative disulfide bond from the N-terminus to the middle of the extracellular domain of these molecules. This is not present in RAMP2.