Journal Title: Current Protein & Peptide Science
Article Title: Exploring New CGRP Family Peptides and their Receptors in Vertebrates
Author(s): Yoshio Takei, Maho Ogoshi and Shigenori Nobata
At least one of three receptor activity-modifying proteins (RAMP1, RAMP2 and RAMP3) can interact with 10 G protein-coupled receptors (GPCRs; nine Family B GPCRs and a Family C GPCR). All three RAMPs interact with the calcitonin (CT) receptor (CTR), the CTR-like receptor (CLR), the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) 1 (VPAC1) and the VPAC2 receptor, which are all Family B GPCRs. Three RAMPs enable CTR to function as three heterodimeric receptors for amylin, which is a feeding suppression peptide. These RAMPs also transport the CLR to the cell surface, where they function as a CT gene-related peptide (CGRP) receptor (CLR/RAMP1 heterodimer) and two adrenomedullin (AM) receptors (CLR/RAMP2 and CLR/RAMP3 heterodimers). CGRP and AM are potent hypotensive peptides that exert powerful protective effects against multi-organ damage. We recently reported that the third extracellular loop (ECL3) of CLR governs the activation of AM, but not CGRP, signaling in the three CLR/RAMP heterodimers. Furthermore, we showed that in the presence of RAMP2, the eighth helix (helix 8) in the proximal portion of the cytoplasmic C-terminal tail of the CLR, which is thought to be present in all family B GPCRs, participates in receptor signaling. In addition, we demonstrated that overexpression of GPCR kinase (GRK) 2, GRK3 and GRK4 enhances the AM-induced internalization of the CLR/RAMP2 heterodimer. In this review, we describe these studies and consider their implications for other Family B GPCRs that can interact with RAMPs.
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Article Title: Adrenomedullin as a Potential Therapeutic Agent for Inflammatory Bowel Disease
Author(s): Shinya Ashizuka, Haruhiko Inatsu, Kyoko Inagaki-Ohara, Toshihiro Kita and Kazuo Kitamura
Receptor activity-modifying proteins (RAMPs) 1–3, which are classified as type I transmembrane proteins, serve as the partner proteins of several family B GPCRs for physiologically active peptides, including the calcitonin receptor- like receptor (CLR). The properties of the GPCRs are defined by the RAMP and peptide ligand combination. The CLR•RAMP1 heterodimer functions mainly as the calcitonin gene-related peptide (CGRP) receptor, while the CLR•RAMP2 and CLR•RAMP3 heterodimers primarily function as the adrenomedullin 1 and adrenomedullin 2 (AM1 and AM2) receptors, respectively. The crystal structures of the RAMP1 and RAMP2 ectodomains exhibited three-helix bundles, and those of their complexes with the N-terminal extracellular domain of CLR revealed how the two ectodomains associate to form the CGRP and AM1 receptors, respectively. On this structural framework, the various intermolecular interactions of CLR with RAMP1 and RAMP2 result in the distinct shapes of the putative ligand-binding sites, where several residues are uniquely presented. Therefore, the differences in the shapes and the presented residues of the binding sites determine the specificities of the receptors to either CGRP or AM. These structural features of the ectodomains are consistent with mutagenesis results, and are useful to further examine the binding modes of the peptide ligands to the full-length CGRP and AM1 receptors.
Author(s): Shingo Takatori, Yoshito Zamami, Narumi Hashikawa-Hobara and Hiromu Kawasaki
Insulin resistance is defined as a preliminary step of type 2 diabetes mellitus with decreased insulin action evoked by continuous postprandial hyperglycemia, which is provoked by high fat and calories dieting, a lack of physical activity and obesity. In the early phase of type 2 diabetes mellitus, patients have a hyperinsulinemia to compensate deficient insulin action by increased secretion from the pancreas to maintain euglycemia. Then, pancreatic β cells progressively decrease secretion function, resulting in the development of diabetes mellitus with decreased serum insulin levels. Accumulating evidences show that insulin resistance is associated with hypertension. However, the mechanisms underlying hypertension associated with type 2 diabetes mellitus have still unknown. Therefore, to elucidate the mechanisms of insulin resistance-induced hypertension, we investigated that the effects of hyperinsulinemia or hyperglycemia on vascular responses mediated by perivascular nerves including sympathetic adrenergic nerves and calcitonin gene-related peptide (CGRP)-containing nerves (CGRPergic nerves). In this article, we show evidence that insulin resistance-induced hypertension could be resulted from increased density and function of sympathetic nerve, and decreased density and function of CGRPergic nerves. Furthermore, our findings provide a new insight into the research of therapeutic drugs for insulin resistance- induced hypertension.