title: Shared and separate functions of the RAMP-based adrenomedullin receptors.
abstract: Adrenomedullin (AM) is a novel hypotensive peptide that exerts a variety of strongly protective effects against multiorgan damage. AM-specific receptors were first identified as heterodimers composed of calcitonin-receptor-like receptor (CLR), a G protein coupled receptor, and one of two receptor activity-modifying proteins (RAMP2 or RAMP3), which are accessory proteins containing a single transmembrane domain. RAMPs are required for the surface delivery of CLR and the determination of its phenotype. CLR/RAMP2 (AM₁ receptor) is more highly AM-specific than CLR/RAMP3 (AM₂ receptor). Although there have been no reports showing differences in intracellular signaling via the two AM receptors, in vitro studies have shed light on their distinct trafficking and functionality. In addition, the tissue distributions of RAMP2 and RAMP3 differ, and their gene expression is differentially altered under pathophysiological conditions, which is suggestive of the separate roles played by AM₁ and AM₂ receptors in vivo. Both AM and the AM₁ receptor, but not the AM₂ receptor, are crucial for the development of the fetal cardiovascular system and are able to effectively protect against various vascular diseases. However, AM₂ receptors reportedly play an important role in maintaining a normal body weight in old age and may be involved in immune function. In this review article, we focus on the shared and separate functions of the AM receptor subtypes and also discuss the potential for related drug discovery. In addition, we mention their possible function as receptors for AM2 (or intermedin), an AM-related peptide whose biological functions are similar to those of AM.
authors.affiliation: Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, Miyazaki 889-1692, Japan. kuwasako@fc.miyazaki-u.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuwasako
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nagata
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hikosaka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Takei
authors.forename: Johji
authors.initials: J
authors.lastname: Kato
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism; D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D058286:Calcitonin Receptor-Like Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D021381:Protein Transport; D051381:Rats; D055647:Rats, Transgenic; D058263:Receptor Activity-Modifying Protein 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058264:Receptor Activity-Modifying Protein 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058265:Receptors, Adrenomedullin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D058286:Calcitonin Receptor-Like Protein; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide