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 AM₁ and AM₂ receptors, respectively. In addition, AM has appreciable affinity for the CGRP₁ receptor, composed of CL and RAMP1. The AM₁ 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 βCGRP. 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 βCGRP might be able to activate both CGRP ₁ and AM₂ receptors and AM could activate both AM ₁ and AM₂ receptors as well as CGRP₁ 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. Copyright © 2004 Humana Press Inc. All rights of any nature whatsoever reserved.