RAMP3
Receptor activity-modifying protein 3 precursor (Calcitonin-receptor-like receptor activity-modifying protein 3) (CRLR activity-modifying protein 3)
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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.
MeSH Terms
- Adrenomedullin
- Aging
- Amino Acid Sequence
- Animals
- Body Weight
- Calcitonin Gene-Related Peptide
- Calcitonin Receptor-Like Protein
- Cardiovascular Diseases
- Cell Line
- Gene Expression
- Humans
- Mice
- Mice, Transgenic
- Molecular Sequence Data
- Protein Transport
- Rats
- Rats, Transgenic
- Receptor Activity-Modifying Protein 2
- Receptor Activity-Modifying Protein 3
- Receptors, Adrenomedullin
- Receptors, Calcitonin
- Sequence Alignment
- Signal Transduction
RAMPs (receptor activity modifying proteins) impart remarkable effects on G protein-coupled receptor (GPCR) signaling. First identified through an interaction with the calcitonin receptor-like receptor (CLR), these single transmembrane proteins are now known to modulate the in vitro ligand binding affinity, trafficking, and second messenger pathways of numerous GPCRs. Consequently, the receptor-RAMP interface represents an attractive pharmacological target for the treatment of disease. Although the three known mammalian RAMPs differ in their sequences and tissue expression, results from in vitro biochemical and pharmacological studies suggest that they have overlapping effects on the GPCRs with which they interact. Therefore, to determine whether RAMP2 and RAMP3 have distinct functions in vivo, we generated mice with targeted deletions of either the RAMP2 or RAMP3 gene. Strikingly, we found that, although RAMP2 is required for survival, mice that lack RAMP3 appear normal until old age, at which point they have decreased weight. In addition, mice with reduced expression of RAMP2 (but not RAMP3) display remarkable subfertility. Thus, each gene has functions in vivo that cannot be accomplished by the other. Because RAMP2, RAMP3, and CLR transduce the signaling of the two potent vasodilators adrenomedullin and calcitonin gene-related peptide, we tested the effects of our genetic modifications on blood pressure, and no effects were detected. Nevertheless, our studies reveal that RAMP2 and RAMP3 have distinct physiological functions throughout embryogenesis, adulthood, and old age, and the mice we have generated provide novel genetic tools to further explore the utility of the receptor-RAMP interface as a pharmacological target.
MeSH Terms
- Adrenomedullin
- Aging
- Animals
- Blood Pressure
- Calcitonin Gene-Related Peptide
- Calcitonin Receptor-Like Protein
- Gene Deletion
- Gene Expression Regulation, Developmental
- Heart Rate
- Heterozygote
- Intracellular Signaling Peptides and Proteins
- Ligands
- Membrane Proteins
- Mice
- Protein Binding
- Receptor Activity-Modifying Protein 2
- Receptor Activity-Modifying Protein 3
- Receptor Activity-Modifying Proteins
- Receptors, Calcitonin