Adrenomedullin receptors: molecular identity and function Debbie L. Hay a, *, David M. Smith b a School of Life Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK b AstraZeneca, CVGI, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK Received 12 April 2001; received in revised form 21 June 2001; accepted 21 June 2001 Abstract Since its discovery in 1993 adrenomedullin (AM) has been the subject over 600 published articles. This multifunctional peptide has powerful vasodilator actions and recent evidence from AM gene-deleted mice suggest that AM plays an essential role in vascular development. However the lack of valid AM receptor clones and non-peptide receptor ligands has considerably slowed research progress on this important peptide. In this review we have focused on the proposition that the calcitonin receptor-like receptor (CRLR) is a receptor both for AM and the related vasoactive peptide calcitonin gene-related peptide (CGRP). The receptor activity modifying proteins (RAMPs) that are essential for defining CRLR pharmacology will also be discussed. We will describe how AM receptors have been reported to signal and be regulated and to consider whether further receptors for AM beyond CRLR/RAMP combinations might exist. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Adrenomedullin receptors; CGRP receptors; CRLR; RAMPs 1. Adrenomedullin AM is a multifunctional regulatory peptide, first ex- tracted from pheochromocytoma and synthesized from a larger precursor, termed preproadrenomedullin [58]. Human AM is a 52 amino acid peptide with a single disulphide bridge located between residues 16 and 21 and an amidated tyrosine at its carboxy terminus. This structure is conserved across species, the rat peptide only differing by 6 substitu- tions and two deletions compared to the human peptide. Some (24%) homology with the powerful vasodilator pep- tide CGRP and the characteristic ring formed by the disul- phide bridge means that AM is an additional member of the calcitonin/CGRP/amylin family of peptides [41]. Elevated circulating AM levels have been identified in a variety of cardiovascular, endocrine and renal disorders [41]. Particularly high levels are evident in septic shock, suggesting that AM may be involved in the homeostasis of blood pressure [72]. In support of this, AM has well estab- lished paracrine vascular cell effects including elevation of cAMP levels in vascular smooth muscle cells and nitric oxide production in endothelial cells [42,47,50]. A range of genetic approaches have been employed to more precisely define the physiological role of AM. Mice specifically engineered to overexpress AM in the vascula- ture exhibit a decreased mean blood pressure and less sus- ceptibility to vascular injury compared to control littermates [92]. AM gene transfer into rat models of cardiac and renal disease states caused significant attenuation of the disease pathology [102]. Furthermore, recent data from AM knock- out mice provides us with the most convincing information to date that AM is an essential vascular peptide [38]. Mice engineered to lack a functional AM gene are characterized by embryonic lethality at midgestation. Close examination of the embryos revealed severe generalized edema (which is often associated with cardiovascular abnormalities), abnor- mal major vessel formation and decreased heart size [8]. Interestingly one group showed that embryos could be res- cued by osmotic mini pump administration of AM [38]. In addition, AM has renal, reproductive and gastric ef- fects, acting both centrally and peripherally and is expressed in many cell lines including tumor-derived, fibroblast and cells of immune function suggesting a wide role for AM [41]. Production of AM from tumor cell lines led to the suggestion that AM might function as a paracrine/autocrine regulator of growth. Indeed AM can stimulate growth in tumor cells and we have shown that AM stimulates DNA * Corresponding author. Tel.: +44-121-359-3611; fax: +44-121- 359-5142. E-mail address: d.hay@ic.ac.uk (D.L. Hay). Peptides 22 (2001) 1753–1763 0196-9781/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0196-9781(01)00532-0