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Description

AM is a potent hypotensive peptide synthesized in the vasculature and various tissues. It is a promising drug target for hypertension and cardiac diseases. AM was isolated and identified from human pheochromocytoma tissue in 1993 by monitoring the activity the elevating intracellular cAMP in rat platelets.

Structure and conformation

Human preproAM consists of 185 aa residues and contains a 21-aa residue signal peptide. AM shares the structural homology of an intramolecular ring structure and has C-terminal amidation with the calcitonin gene-related peptide (CGRP) and amylin. Therefore, AM is considered to be a member of the CGRP family. The sequence identities between AM and other members are not high, including 20% in humans. ProAM includes a unique sequence of 20 aa residues followed by a typical amidation signal, Gly-Lys-Arg. This peptide with an amidated C-terminus is termed proadrenomedullin N-terminal 20 peptide (PAMP). AM is conserved among various vertebrate species, including teleost fish, though the sequence identities are low among species. The sequence of the disulfide ring region and the following C-terminal region are highly conserved in tetrapods, but they vary in teleost fish. Teleost fish possess two types of paralogous am genes: am1 and am4. A mature human AM consists of 52 aa residues and contains a ring structure formed by the intramolecular disulfide bond between cysteine-16 and cysteine-21. The tyrosine residue of the carboxyl end is amidated according to the subsequent amidation signal.

Questions And Answer

• Synthesis and release

  The AM synthesis and release are stimulated by interleukin-1 (IL-1β), tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS). AM production is increased by inflammatory cytokines and NO, possibly mediated by NF-IL6. The expression of ADM is also induced by hypoxia, ischemia, and oxidative stress. Several conflicting results have been reported regarding the effect of mechanical stimuli on ADM expression, but the existence of consensus sequences for the shear stress responsive element (SSRE) in ADM suggests that AM synthesis is influenced by these stimuli. AM secretion from vascular endothelial cells and smooth muscle cells is stimulated by various substances such as angiotensin II, thyroid hormone, and steroid hormones, including aldosterone and glucocorticoids.;

• Receptors

  A functional AM receptor is derived from the calcitonin receptor-like receptor (CLR), whose phenotype is determined by coexpression with receptor activity-modifying proteins (RAMPs). The coexpression of CLR with RAMP2 or RAMP3 produces a receptor for AM, whereas coexpression with RAMP1 results in the CGRP receptor. RAMP2 and RAMP3 are indistinguishable in terms of AM binding, and the differential roles of the CLR/RAMP2 and CLR/RAMP3 receptors have not been fully clarified. CLR is a seventransmembrane-domain GPCR consisting of 474–548 aa residues in mammals; it shares 55% sequence identity with the CT receptor. RAMP is a single-transmembrane accessory protein that regulates the activities of several GPCRs. Besides contributing to receptor specificity, RAMPs are required for the transportation of CLRs from the endoplasmic reticulum to the plasma membrane. Three types of RAMPs consisting of 148–175 aa residues exist in mammals, and five types have been identified in teleost fish. A functional AM receptor requires another accessory protein, the receptor component protein (RCP).;

• Biological functions

  AM has a wide range of biological functions. Receptor expression is detected in the vascular smooth muscle cells, vascular endothelial cells, microvessels, heart, lung, spleen, fat, and kidney. The main functions of AM are vasodilation, hypotension, angiogenesis, and the regulation of fluid and electrolyte homeostasis. AM is also synthesized in the hypothalamus and induces oxytocin release. In nonmammalian species, AM decreases blood pressure by intravenous injection in eels.;

• Clinical implications

  AM is linked to a considerable number of diseases such as hypertension, congestive heart failure, ischemic heart injury, pulmonary hypertension, sepsis, cancers, renal impairment, and diabetes. Elevated plasma levels of AM are useful in assessing the progression of these diseases. AM has cardioprotective and vasoprotective roles in pathophysiological conditions; therefore, the therapeutic use of AM is considered to be promising in both acute-phase disorders and chronic diseases. Circulating AM is also increased after tissue transplantation, suggesting its protective role against oxidative damage. AM is abundantly expressed in tumor cells and is considered to be involved in carcinogenesis, the promotion of tumor proliferation, angiogenesis, and the inhibition of apoptosis.;

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