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      Biochemical, Anatomical, and Pharmacological Characterization of Calcitonin-Type Neuropeptides in Starfish: Discovery of an Ancient Role as Muscle Relaxants

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          Abstract

          Calcitonin (CT) is a peptide hormone released by the thyroid gland that regulates blood Ca 2+ levels in mammals. The CT gene is alternatively spliced, with one transcript encoding CT and another transcript encoding the CT-like neuropeptide calcitonin-gene related peptide (α-CGRP), which is a powerful vasodilator. Other CT-related peptides in vertebrates include adrenomedullin, amylin, and intermedin, which also act as smooth muscle relaxants. The evolutionary origin of CT-type peptides has been traced to the bilaterian common ancestor of protostomes and deuterostomes and a CT-like peptide (DH31) has been identified as a diuretic hormone in some insect species. However, little is known about the physiological roles of CT-type peptides in other invertebrates. Here we characterized a CT-type neuropeptide in a deuterostomian invertebrate—the starfish Asterias rubens (Phylum Echinodermata). A CT-type precursor cDNA (ArCTP) was sequenced and the predicted structure of the peptide (ArCT) derived from ArCTP was confirmed using mass spectrometry. The distribution of ArCTP mRNA and the ArCT peptide was investigated using in situ hybridization and immunohistochemistry, respectively, revealing stained cells/processes in the nervous system, digestive system, and muscular organs, including the apical muscle and tube feet. Investigation of the effects of synthetic ArCT on in vitro preparations of the apical muscle and tube feet revealed that it acts as a relaxant, causing dose-dependent reversal of acetylcholine-induced contraction. Furthermore, a muscle relaxant present in whole-animal extracts of another starfish species, Patiria pectinifera, was identified as an ortholog of ArCT and named PpCT. Consistent with the expression pattern of ArCTP in A. rubens, RT-qPCR revealed that in P. pectinifera the PpCT precursor transcript is more abundant in the radial nerve cords than in other tissues/organs analyzed. In conclusion, our findings indicate that the physiological action of CT-related peptides as muscle relaxants in vertebrates may reflect an evolutionarily ancient role of CT-type neuropeptides that can be traced back to the common ancestor of deuterostomes.

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          Global view of the evolution and diversity of metazoan neuropeptide signaling.

          Neuropeptides are signaling molecules that commonly act via G protein-coupled receptors (GPCRs) and are generated in neurons by proneuropeptide (pNP) cleavage. Present in both cnidarians and bilaterians, neuropeptides represent an ancient and widespread mode of neuronal communication. Due to the inherent difficulties of analyzing highly diverse and repetitive pNPs, the relationships among different families are often elusive. Using similarity-based clustering and sensitive similarity searches, I obtained a global view of metazoan pNP diversity and evolution. Clustering revealed a large and diffuse network of sequences connected by significant sequence similarity encompassing one-quarter of all families. pNPs belonging to this cluster were also identified in the early-branching neuronless animal Trichoplax adhaerens. Clustering of neuropeptide GPCRs identified several orthology groups and allowed the reconstruction of the phyletic distribution of receptor families. GPCR phyletic distribution closely paralleled that of pNPs, indicating extensive conservation and long-term coevolution of receptor-ligand pairs. Receptor orthology and intermediate sequences also revealed the homology of pNPs so far considered unrelated, including allatotropin and orexin. These findings, together with the identification of deuterostome achatin and luqin and protostome opioid pNPs, extended the neuropeptide complement of the urbilaterian. Several pNPs were also identified from the hemichordate Saccoglossus kowalevskii and the cephalochordate Branchiostoma floridae, elucidating pNP evolution in deuterostomes. Receptor-ligand conservation also allowed ligand predictions for many uncharacterized GPCRs from nonmodel species. The reconstruction of the neuropeptide-signaling repertoire at deep nodes of the animal phylogeny allowed the formulation of a testable scenario of the evolution of animal neuroendocrine systems.
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            Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products.

            Alternative processing of RNA transcripts from the calcitonin gene results in the production of distinct mRNAs encoding the hormone calcitonin or a predicted product referred to as calcitonin gene-related peptide (CGRP). The calcitonin mRNA predominates in the thyroid while the CGRP-specific mRNA appears to predominate in the hypothalamus. These observations lead us to propose a model in which developmental regulation of RNA processing is used to increase the diversity of neuroendocrine gene expression.
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              Molecular evolution of peptidergic signaling systems in bilaterians.

              Peptide hormones and their receptors are widespread in metazoans, but the knowledge we have of their evolutionary relationships remains unclear. Recently, accumulating genome sequences from many different species have offered the opportunity to reassess the relationships between protostomian and deuterostomian peptidergic systems (PSs). Here we used sequences of all human rhodopsin and secretin-type G protein-coupled receptors as bait to retrieve potential homologs in the genomes of 15 bilaterian species, including nonchordate deuterostomian and lophotrochozoan species. Our phylogenetic analysis of these receptors revealed 29 well-supported subtrees containing mixed sets of protostomian and deuterostomian sequences. This indicated that many vertebrate and arthropod PSs that were previously thought to be phyla specific are in fact of bilaterian origin. By screening sequence databases for potential peptides, we then reconstructed entire bilaterian peptide families and showed that protostomian and deuterostomian peptides that are ligands of orthologous receptors displayed some similarity at the level of their primary sequence, suggesting an ancient coevolution between peptide and receptor genes. In addition to shedding light on the function of human G protein-coupled receptor PSs, this work presents orthology markers to study ancestral neuron types that were probably present in the last common bilaterian ancestor.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                08 June 2018
                2018
                : 12
                : 382
                Affiliations
                [1] 1School of Biological & Chemical Sciences Queen Mary University of London, London, United Kingdom
                [2] 2Department of Biotechnology, College of Fisheries Sciences Pukyong National University, Busan, South Korea
                [3] 3School of Life Sciences and Proteomics Research Technology Platform University of Warwick, Coventry, United Kingdom
                Author notes

                Edited by: Ian Orchard, University of Toronto Mississauga, Canada

                Reviewed by: Jean-Paul V. Paluzzi, York University, Canada; Simon G. Webster, Bangor University, United Kingdom

                *Correspondence: Nam Gyu Park ngpark@ 123456pknu.ac.kr

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2018.00382
                6002491
                29937709
                daf95635-d1bb-4c0b-a497-96d383f2e04a
                Copyright © 2018 Cai, Kim, Go, Egertová, Zampronio, Jones, Park and Elphick.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 March 2018
                : 18 May 2018
                Page count
                Figures: 14, Tables: 0, Equations: 0, References: 77, Pages: 24, Words: 15888
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council 10.13039/501100000268
                Award ID: BB/M001644/1
                Funded by: Biotechnology and Biological Sciences Research Council 10.13039/501100000268
                Award ID: BB/M001032/1
                Funded by: China Scholarship Council 10.13039/501100004543
                Funded by: Korea Ministry of Environment 10.13039/501100003562
                Award ID: 201300030002
                Categories
                Neuroscience
                Original Research

                Neurosciences
                calcitonin,echinoderm,asterias rubens,starfish,evolution,neuropeptide
                Neurosciences
                calcitonin, echinoderm, asterias rubens, starfish, evolution, neuropeptide

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