Cell and molecular biology of the multifunctional peptide, adrenomedullin

López, Jesús García; Martı́nez, Alfredo

doi:10.1016/s0074-7696(02)21010-4

Cited by 136 publications

(99 citation statements)

References 575 publications

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“…Adrenomedullin (AM) has been known as a member of the calcitonin gene-related peptide (CGRP) family that is composed of CGRP, AM, and amylin (López & Martínez 2001, Brain & Grant 2004, Muff et al 2004). However, AM was found to be diversified in teleost fish and forms an independent subfamily consisting of five paralogs, AM1-AM5 (Ogoshi et al 2003).…”

Section: Introductionmentioning

confidence: 99%

“…CGRP is a neuropeptide in the brain and periphery, which is released from axon terminals innervating the vascular smooth muscles (see Brain & Grant 2004 for review). AM is synthesized in both vascular endothelial cells and smooth muscle cells and exerts potent hypotensive actions by relaxation of microvessels in various peripheral tissues (see López & Martínez (2001) for review). Expression of the AM gene is enhanced in various forms of cardiac failure and renal dysfunction, causing protective actions on the heart and kidney (Tsuruda & Burnett 2002).…”

Section: Introductionmentioning

confidence: 99%

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Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Takei¹,

Hashimoto

Inoue³

et al. 2008

Journal of Endocrinology

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Adrenomedullin 5 (AM5) is a new member of the calcitonin gene-related peptide (CGRP) family identified in teleost fish. Although its presence was suggested in the genome database of mammals, molecular identity and biological function of AM5 have not been examined yet. In this study, we cloned a cDNA encoding AM5 in the pig and examined its cardiovascular and renal effects. Putative mature AM5 was localized in the middle of prohormone and had potential signals for intermolecular ring formation and C-terminal amidation. The AM5 gene was expressed most abundantly in the spleen and thymus. Several AM5 genes were newly identified in the database of mammals, which revealed that the AM5 gene exists in primates, carnivores, and undulates but could not be identified in rodents. In primates, nucleotide deletion occurred in the mature AM5 sequence in anthropoids (human and chimp) during transition from the rhesus monkey. Synthetic mature AM5 injected intravenously into rats induced dose-dependent decreases in arterial pressure at 0 . 1-1 nmol/kg without apparent changes in heart rate. The decrease was maximal in 1 min and AM5 was approximately half as potent as AM. AM5 did not cause significant changes in urine flow and urine Na C concentration at any dose. In contrast to the peripheral vasodepressor action, AM5 injected into the cerebral ventricle dose-dependently increased arterial pressure and heart rate at 0 . 1-1 nmol. The increase reached maximum more quickly after AM5 (5 min) than AM (15-20 min). AM5 added to the culture cells expressing calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of the receptor activitymodifying proteins (RAMPs), the combination of which forms major receptors for the CGRP family, did not induce appreciable increases in cAMP production in any combination, although AM increased it at 10 K10 -10 K9 M when added to the CLR and RAMP2/3 combination. These data indicate that AM5 seems to act on as yet unknown receptor(s) for AM5, other than CLR/CTRCRAMP, to exert central and peripheral cardiovascular actions in mammals.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Takei¹,

Hashimoto

Inoue³

et al. 2008

Journal of Endocrinology

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“…The adm gene is located in mouse chromosome 7 and codes for a preprohormone which, after posttranslational modifications, generates 2 biologically active peptides, AM and proadrenomedullin N-terminal 20 peptide (PAMP). Expression of these peptides is widespread and several functions have been ascribed to these molecules, including vasodilatation, bronchodilatation, hormone secretion regulation, growth modulation, angiogenesis promotion, and antimicrobial activity, among others (1). The receptor system for AM consists of a heterodimer composed of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein (RAMP) type 2 or 3 (2).…”

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confidence: 99%

Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions

Fernández

Serrano²,

Tessarollo³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The adrenomedullin (AM) gene, adm, is widely expressed in the central nervous system (CNS) and several functions have been suggested for brain AM. Until now, a formal confirmation of these actions using genetic models has been elusive since the systemic adm knockout results in embryo lethality. We have built a conditional knockout mouse model using the Cre/loxP approach. When crossed with transgenic mice expressing the Cre recombinase under the tubulin T␣-1 promoter, we obtained animals with no AM expression in the CNS but normal levels in other organs. These animals lead normal lives and do not present any gross morphological defect. Specific areas of the brain of animals lacking CNS AM contain hyperpolymerized tubulin, a consequence of AM downregulation. Behavioral analysis shows that mice with no AM in their brain have impaired motor coordination and are hyperactive and overanxious when compared to their wild-type littermates. Treatment with methylphenidate, haloperidol, and diazepam did not show differences between genotypes. Circulating levels of adrenocorticotropic hormone and corticosterone were similar in knockout and wild-type mice. Animals with no brain AM were less resistant to hypobaric hypoxia than wild-type mice, demonstrating the neuroprotective function of AM in the CNS. In conclusion, AM exerts a beneficial action in the brain by maintaining homeostasis both under normal and stress conditions. A drenomedullin (AM) is a 52-aa regulatory peptide with structural homology to calcitonin gene-related peptide (CGRP) and amylin. The adm gene is located in mouse chromosome 7 and codes for a preprohormone which, after posttranslational modifications, generates 2 biologically active peptides, AM and proadrenomedullin N-terminal 20 peptide (PAMP). Expression of these peptides is widespread and several functions have been ascribed to these molecules, including vasodilatation, bronchodilatation, hormone secretion regulation, growth modulation, angiogenesis promotion, and antimicrobial activity, among others (1). The receptor system for AM consists of a heterodimer composed of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein (RAMP) type 2 or 3 (2).In the CNS, AM was initially found in the hypothalamus (3), but later on it became clear that this peptide is expressed throughout the whole brain (4). Components of the AM receptor system are also found in most areas of the brain (5), providing an anatomical basis for the implication of AM in brain physiology. Receptor autoradiography studies have shown that AM is able to bind to many areas of the brain, as well (6). Recently, a new member of the CGRP/AM peptide family, with a peptide sequence similar to AM but coded by a different gene, has been reported and named AM2 or intermedin. This peptide has similar actions and distribution in the brain to original AM (7).Several observations suggest that AM could act as a neurotransmitter or neuromodulator. For instance, direct injection of AM in the CNS induces vasoconstriction (8), an incre...

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“…6) and the growth promoting effect on several normal and neoplastic cells (reviewed in refs. 3,7). Due to the rather low levels of circulating AM, it is commonly accepted that this peptide acts in an autocrine-paracrine manner (3,6).…”

Section: Introductionmentioning

confidence: 99%

“…2,3). AM acts via a calcitonin receptorlike receptor (CRLR), whose selectivity for AM depends on its interaction with a family of receptor activity modifying proteins (RAMPs): RAMP1 generates CGRP1 receptors, while RAMP2 and RAMP3 give rise to two selective AM receptors, provisionally named AM1 and AM2 (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

Gene silencing of human RAMP2 mediated by short-interfering RNA

Albertin

Ruggero²,

Guidolin³

et al. 2006

Int J Mol Med

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Abstract. Adrenomedullin (AM) is a regulatory peptide widely expressed, along its receptors, in cells and tissues, of which it controls many basic and specific functions acting in an autocrine-paracrine manner. However, the unequivocal demonstration of the physiological relevance of the regulatory role of AM would require the study of cells where the endogenous AM system has been suppressed. For this task we developed a technique to silence the AM gene in human umbilical vein endothelial cells (HUVECs) and the human embryonal kidney cell line (HEK-293). AM acts via two subtypes of receptor, named AM1 and AM2, which derive from the interaction of the calcitonin receptor-like receptors with two chaperones, called receptor activity modifying proteins (RAMP2 and RAMP3). Hence, we developed a protocol to suppress the human AM1 receptor by silencing the RAMP2 gene by transfection with short interfering RNAs (siRNAs). HUVECs were transfected using a new Ambion transfection reagent. RAMP2 gene silencing was determined in HUVECs by measuring RAMP2 mRNA levels in transfected and control cells by realtime polymerase chain reaction. The RAMP2 gene silencing was ~60% and was observed 48 h after transfection. Matrigel assay in vitro was carried out to evaluate the effects of siRNA sequences. HUVECs cells were plated on matrigel and the analysis of capillary-like tubule formation showed that the cells were viable. The knockdown of the RAMP2 gene decreased the formation of tubes in response to 10 -8 M AM. The conclusion is drawn that siRNA technology can be successfully used in the investigations on AM and AM receptor functions.

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Cell and molecular biology of the multifunctional peptide, adrenomedullin

Cited by 136 publications

References 575 publications

Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions

Gene silencing of human RAMP2 mediated by short-interfering RNA

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