Adrenomedullin

Adrenomedullin
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsADM ; AM
External IDsOMIM: 103275 MGI: 108058 HomoloGene: 873 GeneCards: ADM Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez13311535
EnsemblENSG00000148926ENSMUSG00000030790
UniProtP35318P97297
RefSeq (mRNA)NM_001124NM_009627
RefSeq (protein)NP_001115NP_033757
Location (UCSC)Chr 11:
10.33 – 10.33 Mb		Chr 7:
110.63 – 110.63 Mb
PubMed search

Adrenomedullin (ADM or AM) is a peptide hormone that in humans is encoded by the ADM gene. It is an ubiquitously expressed peptide initially isolated from pheochromyctoma, a tumor of the adrenal medulla (hence the name).[1] A second peptide AM2 has been identified, exhibiting a similar functions.[2] It was discovered in 1993.

Function

Adrenomedullin consists of 52 amino acids, has 1 intramolecular disulfide bond, and shows a slight homology with the calcitonin gene-related peptide (CGRP). It may function as a hormone in circulation control because it is found in blood in a considerable concentration. The precursor, called preproadrenomedullin, is 185 amino acids long. By RNA-blot analysis, human adrenomedullin mRNA was found to be highly expressed in several tissues.[3]

AM was initially identified as a vasodilator, some have cited this as the most potent endogenous vasodilatory peptide found in the body. Differences in opinion regarding the ability of AM to relax vascular tone arises from the differences in the model system used.[4] Other effects of AM include upregulating angiogenesis and increasing the tolerance of cells to oxidative stress and hypoxic injury. AM 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 potential of cancerous cells to extend their blood supply and cause cell proliferation.

Peptide

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 (mature) and the glycated form (inactive, with the latter comprising the major form (85%). The measured to have a plasma half-life of 22min, mean clearance rate of 274 mL/kg/min, and apparent volume of distribution of 880+/- 150 mL/kg.[5] Mature AM is metabolised via aminopeptidase action.

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 of which transduce the effect of hormone binding to intracellular signaling 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.[6][7]

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,[8] 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.[9] 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.[10]

References

  1. ↑ Kitamura K, Kato J, Kawamoto M, Tanaka M, Chino N, Kangawa K, Eto T (March 1998). "The intermediate form of glycine-extended adrenomedullin is the major circulating molecular form in human plasma". Biochem. Biophys. Res. Commun. 244 (2): 551–5. doi:10.1006/bbrc.1998.8310. PMID 9514956.
  2. ↑ Fujisawa Y, Nagai Y, Miyatake A, Takei Y, Miura K, Shoukouji T, Nishiyama A, Kimura S, Abe Y (August 2004). "Renal effects of a new member of adrenomedullin family, adrenomedullin2, in rats". Eur. J. Pharmacol. 497 (1): 75–80. doi:10.1016/j.ejphar.2004.06.039. PMID 15321737.
  3. ↑ "Entrez Gene: Adrenomedullin".
  4. ↑ Hamid SA, Baxter GF (February 2005). "Adrenomedullin: regulator of systemic and cardiac homeostasis in acute myocardial infarction". Pharmacol. Ther. 105 (2): 95–112. doi:10.1016/j.pharmthera.2004.08.012. PMID 15670621.
  5. ↑ Meeran K, O'Shea D, Upton PD, Small CJ, Ghatei MA, Byfield PH, Bloom SR (January 1997). "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. doi:10.1210/jcem.82.1.3656. PMID 8989240.
  6. ↑ McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (May 1998). "RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor". Nature 393 (6683): 333–9. doi:10.1038/30666. PMID 9620797.
  7. ↑ Hay DL, Poyner DR, Sexton PM (January 2006). "GPCR modulation by RAMPs". Pharmacol. Ther. 109 (1-2): 173–97. doi:10.1016/j.pharmthera.2005.06.015. PMID 16111761.
  8. ↑ Kapas S, Catt KJ, Clark AJ (October 1995). "Cloning and expression of cDNA encoding a rat adrenomedullin receptor". J. Biol. Chem. 270 (43): 25344–7. doi:10.1074/jbc.270.43.25344. PMID 7592696.
  9. ↑ Kadmiel M, Fritz-Six K, Pacharne S, Richards GO, Li M, Skerry TM, Caron KM (July 2011). "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. doi:10.1210/me.2010-0400. PMC 3125095. PMID 21566080.
  10. ↑ Dackor R, Fritz-Six K, Smithies O, Caron K (June 2007). "Receptor activity-modifying proteins 2 and 3 have distinct physiological functions from embryogenesis to old age". J. Biol. Chem. 282 (25): 18094–9. doi:10.1074/jbc.M703544200. PMID 17470425.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.