Biology:Adrenomedullin
 Generic protein structure example |
Adrenomedullin (ADM or AM) is a vasodilator peptide hormone of uncertain significance in human health and disease. It was initially isolated in 1993 from a pheochromocytoma, a tumor of the adrenal medulla: hence the name.[1]
In humans ADM is encoded by the ADM gene. ADM is a peptide expressed by all tissues, and found in the circulation. A similar peptide named adreomedullin2 was reported in rats in 2004 which exhibits a similar function.[2]
Function
Adrenomedullin may function as a hormone in the circulation control because it is found in blood in a considerable concentration. It was initially identified as a vasodilator, and some argued that it is the most potent endogenous vasodilatory peptide found in the body. Differences in opinion regarding the ability of AM to relax vascular tone may arise from the differences in the model system used.[3]
Other effects of AM include stimulating the growth of new blood vessels (angiogenesis) and increasing the tolerance of cells to oxidative stress and hypoxic injury. Adrenomedullin is seen as a positive influence in diseases such as hypertension, myocardial infarction, chronic obstructive pulmonary disease and other cardiovascular diseases, whereas it can be seen as a negative factor in potentiating the ability of cancerous cells to extend their blood supply and thereby enable further cell proliferation.[citation needed]
Peptide
Adrenomedullin consists of 52 amino acids, has 1 intramolecular disulfide bond, and shows a slight homology with the calcitonin gene-related peptide (CGRP). The precursor, called preproadrenomedullin, consists of 185 amino acids and can be cleaved by plasma kallikrein at the Lys-Arg and Arg-Arg sites.[4] By RNA-blot analysis, human adrenomedullin mRNA was found to be expressed in all tissues, and most highly expressed in the placenta, fat cells, lung, pancreatic islets, smooth muscle, and skin.[5]
The human AM gene is localized to a single locus on Chromosome 11 with 4 exons and 3 introns. The AM gene initially codes for a 185-amino acid precursor peptide, that can be differentially excised to form a number of peptides, including an inactive 53-amino acid AM, e PAMP, adrenotensin and AM95-146. Mature human AM is activated to form a 52 amino acid, 6-amino acid ring, that shares moderate structural similarity to the calcitonin family of regulatory peptides (calcitonin, CGRP and amylin). Circulating AM consists of both amidated active form (15%) and the glycated inactive form (85%). It has a plasma half-life of 22min, mean clearance rate of 27.4 mL/kg/min, and apparent volume of distribution of 880 ± 150 mL/kg.[6]
Receptors
Adrenomedullin (AM) exerts its actions through combinations of the calcitonin receptor like receptor (CALCRL) or CLR; and either (Receptor activity-modifying protein) 2 (RAMP2) or RAMP3, (known as AM1 and AM2 receptors respectively). Both transduce the hormone binding to intracellular signaling via second messenger cascades. The AM2 receptor has a low affinity for CGRP, but this is of no physiological relevance. Unlike the classical one ligand-one receptor notion of receptor signalling, the interaction of both CALCRL and RAMP at the membrane is required for AM to mediate its action: neither can bind the hormone (and therefore transduce a signal) alone. Stimulation by AM of its receptor increases production of both cyclic AMP (cAMP) and nitric oxide.[7][8]
Before the discovery of the RAMPs and the identification of heteromeric receptors for the calcitonin family of peptides, a single G Protein coupled Adrenomedullin receptor was identified,[9] but more recent reports have cast doubts as to its importance in the major effects of adrenomedullin. In more recent research, the roles of the AM1 and AM2 receptors have been clarified through studies in genetically manipulated mice. The adrenomedullin knockout is an embryonic lethal phenotype and dies mid gestation from a condition known as hydrops fetalis. The CALCRL or CLR KO mouse recapitulates the same phenotype, as it lacks both the AM1 and AM2 receptors (incidentally confirming the lack of physiological significance for the earlier single protein AM receptor discovered by Kapas). RAMP2 KO mice also recapitulates the same phenotype showing that major physiological effects of AM are transduced by the AM1 receptor. Even the heterozygote RAMP 2 mice have disturbed physiology with unusual bone and mammary gland defects, and very aberrant endocrinology, leading to poor fertility and lactation problems.[10] What is very surprising is that the effect of deletion of RAMP3 has no deleterious effects and seems to confer advantages due to higher than normal bone mass, and reduced weight gain in older age.[11]
References
- ↑ "The intermediate form of glycine-extended adrenomedullin is the major circulating molecular form in human plasma". Biochem. Biophys. Res. Commun. 244 (2): 551–5. March 1998. doi:10.1006/bbrc.1998.8310. PMID 9514956.
- ↑ "Renal effects of a new member of adrenomedullin family, adrenomedullin2, in rats". Eur. J. Pharmacol. 497 (1): 75–80. August 2004. doi:10.1016/j.ejphar.2004.06.039. PMID 15321737.
- ↑ "Adrenomedullin: regulator of systemic and cardiac homeostasis in acute myocardial infarction". Pharmacol. Ther. 105 (2): 95–112. February 2005. doi:10.1016/j.pharmthera.2004.08.012. PMID 15670621.
- ↑ Verweij, Niek; Mahmud, Hasan; Leach, Irene Mateo; de Boer, Rudolf A.; Brouwers, Frank P.; Yu, Hongjuan; Asselbergs, Folkert W.; Struck, Joachim et al. (2013). "Genome-Wide Association Study on Plasma Levels of Midregional-Proadrenomedullin and C-Terminal-Pro-Endothelin-1". Hypertension (Ovid Technologies (Wolters Kluwer Health)) 61 (3): 602–608. doi:10.1161/hypertensionaha.111.203117. ISSN 0194-911X. PMID 23381795.
- ↑ "Entrez Gene: Adrenomedullin". https://www.ncbi.nlm.nih.gov/gene/133.
- ↑ "Circulating adrenomedullin does not regulate systemic blood pressure but increases plasma prolactin after intravenous infusion in humans: a pharmacokinetic study". J. Clin. Endocrinol. Metab. 82 (1): 95–100. January 1997. doi:10.1210/jcem.82.1.3656. PMID 8989240.
- ↑ "RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor". Nature 393 (6683): 333–9. May 1998. doi:10.1038/30666. PMID 9620797. Bibcode: 1998Natur.393..333M.
- ↑ "GPCR modulation by RAMPs". Pharmacol. Ther. 109 (1–2): 173–97. January 2006. doi:10.1016/j.pharmthera.2005.06.015. PMID 16111761.
- ↑ "Cloning and expression of cDNA encoding a rat adrenomedullin receptor". J. Biol. Chem. 270 (43): 25344–7. October 1995. doi:10.1074/jbc.270.43.25344. PMID 7592696.
- ↑ "Research resource: Haploinsufficiency of receptor activity-modifying protein-2 (RAMP2) causes reduced fertility, hyperprolactinemia, skeletal abnormalities, and endocrine dysfunction in mice". Mol. Endocrinol. 25 (7): 1244–53. July 2011. doi:10.1210/me.2010-0400. PMID 21566080.
- ↑ "Receptor activity-modifying proteins 2 and 3 have distinct physiological functions from embryogenesis to old age". J. Biol. Chem. 282 (25): 18094–9. June 2007. doi:10.1074/jbc.M703544200. PMID 17470425.
Further reading
- "RAMPs: 5 years on, where to now?". Trends Pharmacol. Sci. 24 (11): 596–601. November 2003. doi:10.1016/j.tips.2003.09.001. PMID 14607083.
- "Glycine-extended adrenomedullin exerts vasodilator effect through amidation in the rat aorta". Regul. Pept. 113 (1–3): 109–14. May 2003. doi:10.1016/s0167-0115(03)00002-8. PMID 12686469.
- "Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels". Br J Clin Pharmacol 44 (1): 57–60. July 1997. doi:10.1046/j.1365-2125.1997.00622.x. PMID 9241097.
External links
- Adrenomedullin at the US National Library of Medicine Medical Subject Headings (MeSH)
- Human ADM genome location and ADM gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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