HGNC Approved Gene Symbol: ADM
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:10,305,073-10,307,397 (from NCBI)
The ADM gene encodes for a preprohormone, which is posttranslationally modified to generate 2 biologically active peptides: adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP). Expression of these peptides is widespread, and they have several functions, including vasodilatation, bronchodilatation, hormone secretion regulation, growth modulation, angiogenesis promotion, and antimicrobial activity, among others (Fernandez et al., 2008).
Adrenomedullin, a hypotensive peptide found in human pheochromocytoma, consists of 52 amino acids, has 1 intramolecular disulfide bond, and shows slight homology with the calcitonin gene-related peptide (CGRP; 114130). It may function as a hormone in circulation control because it is found in blood in a considerable concentration. Kitamura et al. (1993) constructed a cDNA library of pheochromocytoma and isolated therefrom a cDNA clone encoding an adrenomedullin precursor. 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, including adrenal medulla, cardiac ventricle, lung, and kidney, as well as pheochromocytoma.
Richards et al. (1996) reviewed information accumulated on adrenomedullin since its original description by Kitamura et al. (1993).
Udono et al. (2001) explored the effects of hypoxia on the production and secretion of adrenomedullin and endothelin-1 (EDN1; 131240) in human retinal pigment epithelial (RPE) cells. They found that ADM mRNA levels and immunoreactive ADM levels in the medium were increased by hypoxia in all 3 RPE cell lines studied. Immunoreactive EDN1 was detected in 2 cultured media. Hypoxia treatment for 28 hours increased immunoreactive EDN1 levels approximately 1.3-fold in 1 cultured cell medium but decreased it in 2 cell lines. Treatment with ADM ameliorated the hypoxia-induced decrease in the cell number. Exogenous EDN1 had no significant effect on the number of cells under normoxia or hypoxia. Udono et al. (2001) concluded that the ADM induced by hypoxia may have protective roles against hypoxic cell damage in RPE cells.
McLatchie et al. (1998) demonstrated that a complex consisting of receptor activity-modifying protein-2 (RAMP2; 605154) and calcitonin receptor-like receptor (CRLR; 114190) can function as an adrenomedullin receptor. To investigate whether ADM has implications as a pathophysiologic substance in pregnancy-induced hypertension, Makino et al. (2001) measured the changes of expression of RAMP2 and CRLR in fetomaternal tissues in normotensive pregnant women and pregnancy-induced hypertensive women by Northern blot analysis. RAMP2 and CRLR mRNA was significantly decreased in the umbilical artery and uterus of the patients with pregnancy-induced hypertension. On the other hand, RAMP2 mRNA was significantly increased in the fetal membrane of the patients with pregnancy-induced hypertension. In addition, there was a significant negative correlation between the RAMP2 mRNA levels in the umbilical artery and uterine muscle and blood pressure. However, there was no correlation between the mRNA level and blood pressure in fetal membrane and placenta, suggesting that there is no close relationship to the pathogenesis in pregnancy-induced hypertension. These findings suggested that the reduced expression of RAMP2 and CRLR functioning as components of an adrenomedullin receptor in umbilical artery and uterus may have some role in pregnancy-induced hypertension.
By immunohistochemical analysis, Ma et al. (2006) found that adrenomedullin was widely distributed in nociceptors of dorsal root ganglion and in axon terminals in the superficial dorsal horn of rat spinal cord. Ma et al. (2006) showed that injection of adrenomedullin caused a pain response in rats and that the response involved the PI3 kinase (see PIK3CG; 601232) signaling pathway.
Ishimitsu et al. (1994) found that the genomic ADM DNA consists of 4 exons and 3 introns, with the 5-prime flanking region containing TATA, CAAT, and GC boxes. There are also multiple binding sites for activator protein-2 (AP2TF; 107580) and a cAMP-regulated enhancer element.
By Southern blot analyses of human/hamster somatic hybrid cell lines, Ishimitsu et al. (1994) demonstrated that the ADM gene is represented by a single locus on chromosome 11. Okazaki et al. (1996) mapped the Adm gene to the distal region of mouse chromosome 7, a region that shows syntenic homology to human 11p15-q13; the human ADM gene is probably located at 11p15.4 (van Heyningen and Jones, 1993).
To elucidate the functions of adrenomedullin, Caron and Smithies (2001) replaced the coding region of the Adm gene in mice with a sequence encoding enhanced green fluorescent protein while leaving the Adm promoter intact. They found that Adm -/- embryos die at midgestation with extreme hydrops fetalis and cardiovascular abnormalities, including overdeveloped ventricular trabeculae and underdeveloped arterial walls. These data suggested that genetically determined absence of Adm may be one cause of nonimmune hydrops fetalis (236750) in humans.
Li et al. (2006) found that female Adm +/- mice had reduced fertility characterized by smaller litters, fetal growth restriction, and placental insufficiency. Fetal Adm was expressed in the trophectoderm as early as embryonic day 3.5 in preimplantation blastocysts, and Adm expression was significantly increased in both maternal uterine and fetal cells during the implantation period. Adm +/- females had abnormal implantation spacing and overcrowded conceptuses in the uterine horns. Placentas from growth-restricted embryos showed defects in trophoblast cell invasion and other morphologic defects. Li et al. (2006) concluded that levels of maternal Adm and, to a lesser extent, embryonic Adm play a critical role in implantation, placentation, and fetal growth.
Caron et al. (2007) generated mice with genetically controlled levels of Adm mRNA ranging from 50% to 140% of wildtype levels. These changes in Adm gene expression had no effect on basal blood pressure. Although pregnancy and sepsis increase plasma Adm levels, genetically reducing Adm production did not affect the transient hypotension that occurs during normal pregnancy or hypotension induced by lipopolysaccharide. Reduction of Adm also had no effect on hypertension induced by renin (REN; 179820) overexpression. However, 50% normal expression of Adm enhanced cardiac hypertrophy and renal damage in male, but not female, mice with renin-induced hypertension.
Fernandez et al. (2008) observed that mice with conditional homozygous knockout of the Adm gene in the brain were viable without gross abnormalities. However, they showed impaired motor coordination and were hyperactive and overanxious compared to wildtype littermates. There were no differences in circulating levels of ACTH or corticosterone between knockout and wildtype mice, and both groups of mice responded similarly to stimulant or antianxiolytic medications. Animals with no brain Adm were less resistant to hypobaric hypoxia than wildtype mice, suggesting that Adm has a neuroprotective function. Certain brains regions of knockout mice, including the hippocampus, cerebral cortex, and cerebellum, showed hyperpolymerized tubulin as a consequence of Adm downregulation. Fernandez et al. (2008) concluded that Adm performs a beneficial action in the brain by maintaining homeostasis both under normal and stress conditions.
Caron, K., Hagaman, J., Nishikimi, T., Kim, H.-S., Smithies, O. Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males. Proc. Nat. Acad. Sci. 104: 3420-3425, 2007. [PubMed: 17360661] [Full Text: https://doi.org/10.1073/pnas.0611365104]
Caron, K. M., Smithies, O. Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional adrenomedullin gene. Proc. Nat. Acad. Sci. 98: 615-619, 2001. [PubMed: 11149956] [Full Text: https://doi.org/10.1073/pnas.98.2.615]
Fernandez, A. P., Serrano, J., Tessarollo, L., Cuttitta, F., Martinez, A. Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions. Proc. Nat. Acad. Sci. 105: 12581-12586, 2008. [PubMed: 18723674] [Full Text: https://doi.org/10.1073/pnas.0803174105]
Ishimitsu, T., Kojima, M., Kangawa, K., Hino, J., Matsuoka, H., Kitamura, K., Eto, T., Matsuo, H. Genomic structure of human adrenomedullin gene. Biochem. Biophys. Res. Commun. 203: 631-639, 1994. [PubMed: 8074714] [Full Text: https://doi.org/10.1006/bbrc.1994.2229]
Kitamura, K., Sakata, J., Kangawa, K., Kojima, M., Matsuo, H., Eto, T. Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem. Biophys. Res. Commun. 194: 720-725, 1993. Note: Erratum: Biochem. Biophys. Res. Commun. 202: 643 only, 1994. [PubMed: 7688224] [Full Text: https://doi.org/10.1006/bbrc.1993.1881]
Li, M., Yee, D., Magnuson, T. R., Smithies, O., Caron, K. M. Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice. J. Clin. Invest. 116: 2653-2662, 2006. [PubMed: 16981008] [Full Text: https://doi.org/10.1172/JCI28462]
Ma, W., Chabot, J.-G., Quirion, R. A role for adrenomedullin as a pain-related peptide in the rat. Proc. Nat. Acad. Sci. 103: 16027-16032, 2006. [PubMed: 17043245] [Full Text: https://doi.org/10.1073/pnas.0602488103]
Makino, Y., Shibata, K., Makino, I., Kangawa, K., Kawarabayashi, T. Alteration of the adrenomedullin receptor components gene expression associated with the blood pressure in pregnancy-induced hypertension. J. Clin. Endocr. Metab. 86: 5079-5082, 2001. [PubMed: 11600589] [Full Text: https://doi.org/10.1210/jcem.86.10.8099]
McLatchie, L. M., Fraser, N. J., Main, M. J., Wise, A., Brown, J., Thompson, N., Solari, R., Lee, M. G., Foord, S. M. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393: 333-339, 1998. [PubMed: 9620797] [Full Text: https://doi.org/10.1038/30666]
Okazaki, T., Ogawa, Y., Tamura, N., Mori, K., Isse, N., Aoki, T., Rochelle, J. M., Taketo, M. M., Seldin, M. F., Nakao, K. Genomic organization, expression, and chromosomal mapping of the mouse adrenomedullin gene. Genomics 37: 395-399, 1996. [PubMed: 8938454] [Full Text: https://doi.org/10.1006/geno.1996.0576]
Richards, A. M., Nicholls, M. G., Lewis, L., Lainchbury, J. G. Adrenomedullin. Clin. Sci. (Lond.) 91: 3-16, 1996. Note: Erratum: Clin. Sci. (Lond.) 91: 525 only, 1996. [PubMed: 8774254] [Full Text: https://doi.org/10.1042/cs0910003]
Udono, T., Takahashi, K., Nakayama, M., Yoshinoya, A., Totsune, K., Murakami, O., Durlu, Y. K., Tamai, M., Shibahara, S. Induction of adrenomedullin by hypoxia in cultured retinal pigment epithelial cells. Invest. Ophthal. Vis. Sci. 42: 1080-1086, 2001. [PubMed: 11274089]
van Heyningen, V., Jones, C. Report of the committee on the genetic constitution of chromosome 11.In: Cuticchia, A. J.; Pearson, P. L.; Klinger, H. P. (eds.) : Chromosome coordinating meeting, 1992. Genome Priority Reports, Vol 1. Basel: S. Karger (pub.) 1993. Pp. 365-401.