Adrenomedullin – new perspectives of a potent peptide hormone

Abstract

Adrenomedullin (ADM) is a 52-amino acid multifunctional peptide, which belongs to the calcitonin gene-related peptide (CGRP) superfamily of vasoactive peptide hormones. ADM exhibits a significant vasodilatory potential and plays a key role in various regulatory mechanisms, predominantly in the cardiovascular and lymphatic system. It exerts its effects by activation of the calcitonin receptor-like receptor associated with one of the receptor activity-modifying proteins 2 or 3. ADM was first isolated from human phaeochromocytoma in 1993. Numerous studies revealed a widespread distribution in various tissues and organs, which is reflected by its multiple physiological roles in health and disease. Because of its anti-inflammatory, anti-apoptotic and proliferative properties, ADM exhibits potent protective functions under diverse pathological conditions, but it is also critically involved in tumor progression. ADM has therefore raised great interest in therapeutic applications and several clinical trials already revealed promising results. However, because the receptor activation mode has not yet been fully elucidated, a rational design of potent and selective ligands is still challenging. Detailed information on the binding mode of ADM from a recently reported crystal structure as well as efforts to improve its plasma stability and bioavailability may help to overcome these limitations in the future. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Adrenomedullin in heart failure: pathophysiology and therapeutic application

“…The combination of RAMP 2 or 3 with the calcitonin receptor‐like receptor (CRLR) confers specificity of the receptor for ADM, and thus both RAMPs and CRLR are key in ADM expression . While ADM was first discovered in pheochromocytoma originating from the adrenal medulla (hence the name ‘adrenomedullin’), further investigation showed that it was synthesized by many other tissues/cells, especially endothelial and vascular smooth muscle cells, and due to its small size (6 kDa) diffuses freely between blood and interstitium . By proteolytic fragmentation of the pro‐hormone (pro‐ADM), a glycine‐extended, inactive ADM is formed, which subsequently is enzymatically converted from ADM‐glycine to the biologically active ADM‐amide.…”

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM1 receptor activation

“…Adrenomedullin (ADM) is a peptide hormone consisting of 52 amino acids, which was discovered in 1993 as an isolate of pheochromocytoma tissue . It plays a pivotal regulatory role in various physiological processes, mostly but not exclusively associated with the cardiovascular system . Besides its strong vasodilative properties, it induces angiogenesis as well as lymphangiogenesis, contributes to fluid and electrolyte homeostasis, plays an important role during pregnancy, and possesses antimicrobial properties .…”

“…It plays a pivotal regulatory role in various physiological processes, mostly but not exclusively associated with the cardiovascular system . Besides its strong vasodilative properties, it induces angiogenesis as well as lymphangiogenesis, contributes to fluid and electrolyte homeostasis, plays an important role during pregnancy, and possesses antimicrobial properties . Furthermore, it has been shown that ADM is overexpressed in various cancer types, where it acts as a tumor survival factor .…”

The Impact of Adrenomedullin Thr22 on Selectivity within the Calcitonin Receptor‐like Receptor/Receptor Activity‐Modifying Protein System

“…[1] Since its discovery in 1993 by isolation from human pheochromocytoma tissue, av ariety of physiological implications have been identified. [2,3] ADM plays ac rucial role in the regulation of numerous cardiovascular processes, such as vasodilation,a ngiogenesis, lymph angiogenesis and the reduction of oxidative stress. [4] Furthermore, ADM gene expression was found to be upregulatedd uring pregnancy,b ut also in varioust umor cell lines and malignant tissues.…”

“…[5] Therefore, it is of increasingi mportance as an early-stage biomarker for variousd iseases and as ap otential therapeutic agent. [3,6] The peptides of the CGRP family are able to differentially activate subtypes of the class BGprotein-coupled receptor (GPCR)c alcitonin receptor-like receptor (CLR),w hich are formed by heterodimerization with one of three receptora ctivity-modifying proteins (RAMP 1, 2, or 3). [7] ADM signals primarily through the ADM-1 receptor (AM 1 R, CLR + RAMP2) and the ADM-2 receptor (AM 2 R, CLR + RAMP3), but is also able to activate the CGRP receptor( CGRPR, CLR + RAMP1) with decreased potency.…”