DOCSLIB.ORG

Osteoblast Regulation Via Ligand-Activated Nuclear Trafficking of the Oxytocin Receptor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Osteoblast Regulation Via Ligand-Activated Nuclear Trafficking of the Oxytocin Receptor Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor Adriana Di Benedettoa,b, Li Sunc,d, Carlo G. Zambonine, Roberto Tammaa, Beatrice Nicoa, Cosima D. Calvanoe, Graziana Colaiannia, Yaoting Jic,d, Giorgio Morib, Maria Granoa, Ping Luc,d, Silvia Coluccia, Tony Yuenc,d, Maria I. Newf,1, Alberta Zallonea,2, and Mone Zaidic,d,g,1,2 aDepartment of Basic Medical Science, Neurosciences and Sensory Organs, University of Bari Aldo Moro Medical School, Bari 70126, Italy; bDepartment of Clinical and Experimental Medicine, University of Foggia, Foggia 71122, Italy; cMount Sinai Bone Program and dDepartment of Medicine, Mount Sinai School of Medicine, New York, NY 10029; eDepartment of Chemistry, University of Bari Aldo Moro, Bari 70126, Italy; and Departments of fPediatrics and gStructural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029 Contributed by Maria I. New, October 8, 2014 (sent for review August 27, 2014); reviewed by Xu Cao, Christopher Huang, and Carlos Isales We report that oxytocin (Oxt) receptors (Oxtrs), on stimulation by bisphosphate 3-kinase (Akt/PI3K) (9, 10). Such mechanisms can the ligand Oxt, translocate into the nucleus of osteoblasts, impli- elicit delayed genomic responses. cating this process in the action of Oxt on osteoblast maturation. After being internalized, GPCRs are either recycled back to Sequential immunocytochemistry of intact cells or isolated nucleo- the plasma membrane to resensitize the cell to ligand action or plasts stripped of the outer nuclear membrane showed progressive transported to lysosomes for degradation. Although G proteins nuclear localization of the Oxtr; this nuclear translocation was con- have been found in the Golgi body, endoplasmic reticulum, and firmed by monitoring the movement of Oxtr–EGFP as well as by cytoskeleton (11–13), GPCRs can localize to the nucleus or nuclear immunogold labeling. Nuclear Oxtr localization was conclusively membrane (14–16). For example, on treatment with sphingosine-1- shown by Western immunoblotting and MS of nuclear lysate pro- phosphate (S1P), the S1P receptor subtype 1 can translocate to teins. We found that the passage of Oxtrs into the nucleus was endothelial cell nuclei to activate transcription (17). Likewise, facilitated by successive interactions with β-arrestins (Arrbs), the chemokine receptor 2 (CCR2), expressed in monocyte, has been small GTPase Rab5, importin-β (Kpnb1), and transportin-1 (Tnpo1). shown to interact directly with transportin-1 (Tnpo1) to undergo siRNA-mediated knockdown of Arrb1, Arrb2,orTnpo1 abrogated nuclear localization (18). Cysteine (C)-X-C Receptor 4 (CXCR4) MEDICAL SCIENCES Oxt-induced expression of the osteoblast differentiation genes α α osterix (Sp7), Atf4, bone sialoprotein (Ibsp), and osteocalcin (Bglap) similarly responds to stromal cell-derived factor-1 (SDF-1 )to without affecting Erk phosphorylation. Likewise and again, with- undergo internalization and Tnpo1-mediated nuclear targeting in out affecting pErk, inhibiting Arrb recruitment by mutating Ser prostate cancer cells (19). rich clusters of the nuclear localization signal to Ala abolished nu- Human osteosarcoma and breast cancer cell lines display both clear import and Oxtr-induced gene expression. These studies define cell membrane and nuclear Oxtrs (20). However, the functional a previously unidentified mechanism for Oxtr action on bone and significance of the nuclear localization of the Oxtr or indeed, any open possibilities for direct transcriptional modulation by nuclear G GPCR continues to unravel. Here, we have combined proteomic, protein-coupled receptors. molecular, and cell biological approaches to confirm the translocation of the Oxtr to the nucleus in osteoblasts after Oxt nuclear translocation | G protein-coupled receptor | binding and to study the putative function of this pathway in Oxt- transcriptional regulation induced bone formation. We find that Oxtr nuclear localization is Arrb- and Tnpo1-dependent. Thus, siRNA knockdown of he oxytocin (Oxt) receptor (Oxtr), a member of the rho- Arrb or Tnpo1 inhibits not only nuclear localization but also, Tdopsin-type (class I) family of G protein-coupled receptors the proosteoblastic action of Oxt, interestingly without affect- (GPCRs), responds to the neurohypophyseal hormone Oxt to ing Erk phosphorylation. These findings represent a hitherto stimulate lactation and social bonding (1, 2). More recently, we unrecognized pathway for Oxt action. and others have shown that Oxt also stimulates bone formation directly by interacting with an osteoblastic Oxtr (3, 4). The ge- Significance netic deletion of Oxt or Oxtr in mice thus decreases osteoblast differentiation and bone formation, causing osteopenia (5, 6). We We have shown previously that oxytocin (Oxt), other than believe that this action supports maternal skeletal remineralization regulating lactation and social bonding, is a potent stimulator after the intergenerational transfer of calcium during pregnancy of bone formation by the osteoblast. Here, we present evi- and lactation (5). However, the precise mechanism through dence that this action is exerted through the nuclear localiza- which Oxtr activation translates into increased bone formation tion of the Oxt receptor (Oxtr). Our findings prompt additional remains unclear. studies into the contribution of nuclear Oxtr signaling in reg- ulating lactation and social bonding. Oxt binding to Oxtrs is known to activate both G protein Gαi- and Gαq/11-mediated phospholipase C pathways (7). However, in Author contributions: T.Y., M.I.N., A.Z., and M.Z. designed research; A.D.B., L.S., C.G.Z., common with other GPCRs, prolonged or repetitive agonist R.T., B.N., C.D.C., G.C., Y.J., G.M., and P.L. performed research; A.D.B., L.S., C.G.Z., R.T., stimulation by Oxt results in Oxtr internalization through C.D.C., M.G., S.C., T.Y., A.Z., and M.Z. analyzed data; and T.Y., M.I.N., A.Z., and M.Z. wrote β-arrestin (Arrb). GPCR internalization can activate signaling the paper. pathways quite distinct from those activated by the same Reviewers: X.C., Johns Hopkins School of Medicine; C.H., University of Cambridge; and C.I., Georgia Regents University. receptors resident at the cell surface. Hence, desensitization of The authors declare no conflict of interest. primary G protein-dependent signaling can be followed by a sec- 1 – β To whom correspondence may be addressed. Email: [email protected] or mone. ond wave of Arrb mediated signaling (8). -Arrestins can also [email protected]. recruit signaling proteins that connect GPCRs to various cyto- 2A.Z. and M.Z. contributed equally to this work. plasmic effector pathways, such as mitogen-activated protein This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. kinase (MAPK) and protein kinase B/phosphatidylinositol-4,5- 1073/pnas.1419349111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1419349111 PNAS Early Edition | 1of6 Downloaded by guest on September 25, 2021 Results Considering the newly discovered anabolic function of Oxt in skeletal regulation, we sought to investigate the fate of the os- teoblast Oxtr after Oxt binding. Confocal immunofluorescence microscopy showed that, in primary murine osteoblasts and MC3T3.E1 preosteoblastic cells, exposure to Oxt triggered the nuclear localization of Oxtrs. Under basal unstimulated con- ditions, Oxtrs appeared mainly at the plasma membrane and in − the cytoplasm, whereas 20–40 min after the addition of Oxt (10 8 M), a clear nuclear localization was observed (Fig. 1A). This effect was definitively verified by transmission electron micros- copy using an immunogold-labeled secondary antibody. Again, under basal conditions, immunogold particles corresponding to the anti-Oxtr were observed mainly on the plasma membrane, whereas after Oxt treatment, they progressively moved to the cy- toplasm (∼20 min) and then, the nuclear membrane and nucleus (∼40 min) (Fig. 1B). To exclude potential artifacts arising from the extreme flatness of cultured cells or possible localization of Oxtrs to membrane structures close to the nuclear compartment, we isolated intact nucleoplasts from primary murine osteoblasts. Our technique removes the outer nuclear membrane, yielding a pure fraction of nucleoplasts that are surrounded by the inner but not outer membrane. Nucleoplasts were isolated after stimulation of intact osteoblasts with Oxt (40 min) and stained for Oxtr and importin-β (Kpnb1); the latter is a known inner nuclear membrane and nucleoplasm marker. Confocal microscopy revealed intense Oxtr immunofluorescence localized mainly within the inner nuclear membrane (Fig. 1C). Merged micrographs showed that Oxtr colocalized with Kpnb1, thus confirming the presence of the receptors at the inner nuclear membrane (Fig. 1C). Nuclear lo- calization was further evaluated independently by transfecting − − osteoblasts derived from Oxtr / mice with Oxtr–EGFP fusion plasmid (gift from Bice Chini, The National Research Council, Milan, Italy) with EGFP tagged to the Oxtr carboxyl terminus. − After exposure to Oxt (10 8 M), nucleoplasts were again isolated and marked with the anti-Kpnb1 antibody. Exogenous Oxtr– EGFP was found to localize to the inner nuclear membrane in a pattern that overlapped to an extent with Kpnb1 (Fig. 1D). We also used biochemical and proteomic approaches to de- finitively confirm the nuclear localization observed on micros- copy. Western immunoblotting was used to study the presence of Oxtrs in the cytosolic and nuclear
Load more

Recommended publications
  • Design and Synthesis of Cyclic Analogs of the Kappa Opioid Receptor Antagonist Arodyn
    Design and synthesis of cyclic analogs of the kappa opioid receptor antagonist arodyn By © 2018 Solomon Aguta Gisemba Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Chair: Dr. Blake Peterson Co-Chair: Dr. Jane Aldrich Dr. Michael Rafferty Dr. Teruna Siahaan Dr. Thomas Tolbert Date Defended: 18 April 2018 The dissertation committee for Solomon Aguta Gisemba certifies that this is the approved version of the following dissertation: Design and synthesis of cyclic analogs of the kappa opioid receptor antagonist arodyn Chair: Dr. Blake Peterson Co-Chair: Dr. Jane Aldrich Date Approved: 10 June 2018 ii Abstract Opioid receptors are important therapeutic targets for mood disorders and pain. Kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and 1,2,3 4 8 depression. Arodyn (Ac[Phe ,Arg ,D-Ala ]Dyn A(1-11)-NH2), an acetylated dynorphin A (Dyn A) analog, has demonstrated potent and selective KOR antagonism, but can be rapidly metabolized by proteases. Cyclization of arodyn could enhance metabolic stability and potentially stabilize the bioactive conformation to give potent and selective analogs. Accordingly, novel cyclization strategies utilizing ring closing metathesis (RCM) were pursued. However, side reactions involving olefin isomerization of O-allyl groups limited the scope of the RCM reactions, and their use to explore structure-activity relationships of aromatic residues. Here we developed synthetic methodology in a model dipeptide study to facilitate RCM involving Tyr(All) residues. Optimized conditions that included microwave heating and the use of isomerization suppressants were applied to the synthesis of cyclic arodyn analogs.
    [Show full text]
  • Radial Glia Reveal Complex Regulation by the Neuropeptide Secretoneurin
    Transcriptomic and proteomic characterizations of goldfish (Carassius auratus) radial glia reveal complex regulation by the neuropeptide secretoneurin Dillon Da Fonte Thesis submitted to the Faculty of Graduate and Postdoctoral Studies University of Ottawa in partial fulfillment of the requirements for the Master of Science degree in biology Department of Biology Faculty of Science University of Ottawa © Dillon Da Fonte, Ottawa, Canada, 2016 Acknowledgements Finishing this thesis has been both a challenging and rewarding experience. This accomplishment would not have been possible without the never-ending support of colleagues, friends, family. First, I would like to express my most sincere gratitude to my supervisor and mentor, Dr. Vance Trudeau. Thank you for the opportunities you have given me, this experience has truly solidified my passion for research. I appreciate our many conversations that were enjoyed over a beer – it was truly a memorable experience. I would also like to thank my M.Sc. advisory committee, Dr. Michael Jonz and Dr. Marc Ekker for your time and insightful comments. A special thank you to Dr. Chris Martynuik who taught me the bioinformatics needed to analyze both transcriptomic and proteomic data and for all your help during my time at the University of Florida. I would like to also acknowledge my funding support from University of Ottawa, NSERC, and the Michael Smith Foreign Study Award for supporting my research stay at the University of Florida. To all current and past members of TeamENDO, thank you for the sense of community you all instilled in the lab. Both inside and outside the lab, I have made memories with all of you that I will cherish forever.
    [Show full text]
  • Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands
    Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands By Stephanie Nicole Johnson Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Masters in Science. Chairperson: Dr. Thomas E. Prisinzano Dr. Apurba Dutta Dr. Jeffrey P. Krise Date Defended: May 2, 2017 The Thesis Committee for Stephanie Nicole Johnson certifies that this is the approved version of the following thesis: Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands Chairperson: Dr. Thomas E. Prisinzano Date approved: May 4, 2017 ii Abstract The ability of ligands to differentially regulate the activity of signaling pathways coupled to a receptor potentially enables researchers to optimize therapeutically relevant efficacies, while minimizing activity at pathways that lead to adverse effects. Recent studies have demonstrated the functional selectivity of kappa opioid receptor (KOR) ligands acting at KOR expressed by rat peripheral pain sensing neurons. In addition, KOR signaling leading to antinociception and dysphoria occur via different pathways. Based on this information, it can be hypothesized that a functionally selective KOR agonist would allow researchers to optimize signaling pathways leading to antinociception while simultaneously minimizing activity towards pathways that result in dysphoria. In this study, our goal was to alter the structure of U50,488 such that efficacy was maintained for signaling pathways important for antinociception (inhibition of cAMP accumulation) and minimized for signaling pathways that reduce antinociception. Thus, several compounds based on the U50,488 scaffold were designed, synthesized, and evaluated at KORs. Selected analogues were further evaluated for inhibition of cAMP accumulation, activation of extracellular signal-regulated kinase (ERK), and inhibition of calcitonin gene- related peptide release (CGRP).
    [Show full text]
  • Estrogen Receptor (ER) Expression and Function in the Pregnant Human Myometrium: Estradiol Via Era Activates ERK1/2 Signaling in Term Myometrium
    227 Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERa activates ERK1/2 signaling in term myometrium Toni Welsh1,2, Matrika Johnson1, Lijuan Yi1, Huiqing Tan1, Roksana Rahman1, Amy Merlino1, Tamas Zakar2,3 and Sam Mesiano1 1Department of Reproductive Biology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA 2Mothers and Babies Research Centre, University of Newcastle, Newcastle, New South Wales 2308, Australia 3Department of Obstetrics and Gynaecology, John Hunter Hospital, Newcastle, New South Wales 2305, Australia (Correspondence should be addressed to S Mesiano; Email: [email protected]) Abstract Estrogens are thought to promote labor by increasing inhibition of 26S proteasome activity increased ERa protein the expression of pro-contraction genes in myometrial cells. abundance to detectable levels in term myometrial explants, The specific estrogen receptors ((ERs: ERa and ERb (also however, indicating rapid turnover of ERa protein by known as ESR1 and ESR2)) and G protein-coupled receptor proteasomal processing in the pregnant myometrium. E2 30 (GPR30; also known as G protein-coupled estrogen stimulated rapid extranuclear signaling in myometrial explants, receptor 1)) and signaling pathways that mediate these actions as evidenced by increased extracellularly regulated kinase are not clearly understood. In this study, we identified the ERs (ERK1/2) phosphorylation within 10 min. This effect was expressed in the pregnant human myometrium and determined inhibited by pre-treatment with an ER antagonist, ICI a key extranuclear signaling pathway through which estradiol 182 780, indicating the involvement of ERa. Inhibition of (E2) modulates expression of the gene encoding the oxytocin ERK signaling abrogated the ability of E2 to stimulate OXTR receptor (OXTR), a major pro-contraction protein.
    [Show full text]
  • The Oxytocin/Vasopressin Receptor Family Has at Least Five Members in the Gnathostome Lineage, Including Two Distinct V2 Subtypes
    The oxytocin/vasopressin receptor family has at least five members in the gnathostome lineage, including two distinct V2 subtypes General and Comparative Endocrinology 175(1): 135-143 doi:10.1016/j.ygcen.2011.10.011 Accepted October 20, 2011 E-pub October 28, 2012 Published January 1, 2012 Figshare doi:10.6084/m9.figshare.811860. Shared October 1, 2013 Daniel Ocampo Daza*, Michalina Lewicka¹, Dan Larhammar Department of Neuroscience, Science for Life Laboratory, Uppsala Universitet, Box 593, SE-751 24 Uppsala, Sweden * Corresponding author. E-mail address: [email protected] ¹ Current address: Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden Cite as D. Ocampo Daza, M. Lewicka and D. Larhammar. The oxytocin/vasopressin family has at least five members in the gnathostome lineage, including two distinct V2 subtypes. General and Comparative Endocrinology, 175 (1) (2012) 135-143. This document corresponds to the article as it appeared upon acceptance. You are free to download, print and distribute it for any purposes under a Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/), provided the original work is cited as specified. Errata: The introduction incorrectly states that “the V2 receptor inhibits adenylyl cyclase, thereby reducing the production of cAMP” on page 3. In fact the V2-type vasopressin receptors stimulate adenylyl cyclase and increase the cytosolic cyclic AMP release, see for instance Schöneberg et al., Molecular aspects of vasopressin receptor function, Advances in experimental medicine and biology 449 (1998) 347–58. This mistake was reported in the proofreading phase of pre-publication, but the correction was not carried to the final version of the article.
    [Show full text]
  • G Protein-Coupled Receptors: What a Difference a ‘Partner’ Makes
    Int. J. Mol. Sci. 2014, 15, 1112-1142; doi:10.3390/ijms15011112 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review G Protein-Coupled Receptors: What a Difference a ‘Partner’ Makes Benoît T. Roux 1 and Graeme S. Cottrell 2,* 1 Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK; E-Mail: [email protected] 2 Reading School of Pharmacy, University of Reading, Reading RG6 6UB, UK * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +44-118-378-7027; Fax: +44-118-378-4703. Received: 4 December 2013; in revised form: 20 December 2013 / Accepted: 8 January 2014 / Published: 16 January 2014 Abstract: G protein-coupled receptors (GPCRs) are important cell signaling mediators, involved in essential physiological processes. GPCRs respond to a wide variety of ligands from light to large macromolecules, including hormones and small peptides. Unfortunately, mutations and dysregulation of GPCRs that induce a loss of function or alter expression can lead to disorders that are sometimes lethal. Therefore, the expression, trafficking, signaling and desensitization of GPCRs must be tightly regulated by different cellular systems to prevent disease. Although there is substantial knowledge regarding the mechanisms that regulate the desensitization and down-regulation of GPCRs, less is known about the mechanisms that regulate the trafficking and cell-surface expression of newly synthesized GPCRs. More recently, there is accumulating evidence that suggests certain GPCRs are able to interact with specific proteins that can completely change their fate and function. These interactions add on another level of regulation and flexibility between different tissue/cell-types.
    [Show full text]
  • Analysis of the Indacaterol-Regulated Transcriptome in Human Airway
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/04/13/jpet.118.249292.DC1 1521-0103/366/1/220–236$35.00 https://doi.org/10.1124/jpet.118.249292 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:220–236, July 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the s Adverse and Therapeutic Effects of b2-Adrenoceptor Agonists Dong Yan, Omar Hamed, Taruna Joshi,1 Mahmoud M. Mostafa, Kyla C. Jamieson, Radhika Joshi, Robert Newton, and Mark A. Giembycz Departments of Physiology and Pharmacology (D.Y., O.H., T.J., K.C.J., R.J., M.A.G.) and Cell Biology and Anatomy (M.M.M., R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Received March 22, 2018; accepted April 11, 2018 Downloaded from ABSTRACT The contribution of gene expression changes to the adverse and activity, and positive regulation of neutrophil chemotaxis. The therapeutic effects of b2-adrenoceptor agonists in asthma was general enriched GO term extracellular space was also associ- investigated using human airway epithelial cells as a therapeu- ated with indacaterol-induced genes, and many of those, in- tically relevant target. Operational model-fitting established that cluding CRISPLD2, DMBT1, GAS1, and SOCS3, have putative jpet.aspetjournals.org the long-acting b2-adrenoceptor agonists (LABA) indacaterol, anti-inflammatory, antibacterial, and/or antiviral activity. Numer- salmeterol, formoterol, and picumeterol were full agonists on ous indacaterol-regulated genes were also induced or repressed BEAS-2B cells transfected with a cAMP-response element in BEAS-2B cells and human primary bronchial epithelial cells by reporter but differed in efficacy (indacaterol $ formoterol .
    [Show full text]
  • The Oxytocin Receptor Gene (OXTR) Is Associated with Autism Spectrum Disorder: a Meta-Analysis
    Molecular Psychiatry (2015) 20, 640–646 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp ORIGINAL ARTICLE The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis D LoParo and ID Waldman The oxytocin receptor gene (OXTR) has been studied as a risk factor for autism spectrum disorder (ASD) owing to converging evidence from multiple levels of analysis that oxytocin (OXT) has an important role in the regulation of affiliative behavior and social bonding in both nonhuman mammals and humans. Inconsistency in the effect sizes of the OXTR variants included in association studies render it unclear whether OXTR is truly associated with ASD, and, if so, which OXTR single-nucleotide polymorphisms (SNPs) are associated. Thus, a meta-analytic review of extant studies is needed to determine whether OXTR shows association with ASD, and to elucidate which specific SNPs have a significant effect on ASD. The current meta-analysis of 16 OXTR SNPs included 3941 individuals with ASD from 11 independent samples, although analyses of each individual SNP included a subset of this total. We found significant associations between ASD and the SNPs rs7632287, rs237887, rs2268491 and rs2254298. OXTR was also significantly associated with ASD in a gene-based test. The current meta-analysis is the largest and most comprehensive investigation of the association of OXTR with ASD and the findings suggest directions for future studies of the etiology of ASD. Molecular Psychiatry (2015) 20, 640–646; doi:10.1038/mp.2014.77; published online 5 August 2014 INTRODUCTION sizes.8 Nevertheless, several genes and genomic regions have Autism spectrum disorder (ASD) refers to a group of neuro- shown relatively consistent association with ASD.
    [Show full text]
  • Evolution of Neuropeptide Signalling Systems (Doi:10.1242/Jeb.151092) Maurice R
    © 2018. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2018) 221, jeb193342. doi:10.1242/jeb.193342 CORRECTION Correction: Evolution of neuropeptide signalling systems (doi:10.1242/jeb.151092) Maurice R. Elphick, Olivier Mirabeau and Dan Larhammar There was an error published in J. Exp. Biol. (2018) 221, jeb151092 (doi:10.1242/jeb.151092). In Fig. 2, panels B and C are identical. The correct figure is below. The authors apologise for any inconvenience this may have caused. Journal of Experimental Biology 1 © 2018. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2018) 221, jeb151092. doi:10.1242/jeb.151092 REVIEW Evolution of neuropeptide signalling systems Maurice R. Elphick1,*,‡, Olivier Mirabeau2,* and Dan Larhammar3,* ABSTRACT molecular to the behavioural level (Burbach, 2011; Schoofs et al., Neuropeptides are a diverse class of neuronal signalling molecules 2017; Taghert and Nitabach, 2012; van den Pol, 2012). that regulate physiological processes and behaviour in animals. Among the first neuropeptides to be chemically identified in However, determining the relationships and evolutionary origins of mammals were the hypothalamic neuropeptides vasopressin and the heterogeneous assemblage of neuropeptides identified in a range oxytocin, which act systemically as hormones (e.g. regulating of phyla has presented a huge challenge for comparative physiologists. diuresis and lactation) and act within the brain to influence social Here, we review revolutionary insights into the evolution of behaviour (Donaldson and Young, 2008; Young et al., 2011). neuropeptide signalling that have been obtained recently through Evidence of the evolutionary antiquity of neuropeptide signalling comparative analysis of genome/transcriptome sequence data and by emerged with the molecular identification of neuropeptides in – ‘deorphanisation’ of neuropeptide receptors.
    [Show full text]
  • Multi-Functionality of Proteins Involved in GPCR and G Protein Signaling: Making Sense of Structure–Function Continuum with In
    Cellular and Molecular Life Sciences (2019) 76:4461–4492 https://doi.org/10.1007/s00018-019-03276-1 Cellular andMolecular Life Sciences REVIEW Multi‑functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder‑based proteoforms Alexander V. Fonin1 · April L. Darling2 · Irina M. Kuznetsova1 · Konstantin K. Turoverov1,3 · Vladimir N. Uversky2,4 Received: 5 August 2019 / Revised: 5 August 2019 / Accepted: 12 August 2019 / Published online: 19 August 2019 © Springer Nature Switzerland AG 2019 Abstract GPCR–G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signal- ing cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand–GPCR and GPCR–G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defnes an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR–G protein system represents an illustrative example of the protein structure–function continuum, where structures of the involved proteins represent a complex mosaic of diferently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fne-tuned by various post-translational modifcations and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specifc partners.
    [Show full text]
  • Peripheral Blood Mononuclear Cell Oxytocin and Vasopressin Receptor Expression Positively Correlates with Social and Behavioral
    www.nature.com/scientificreports OPEN Peripheral Blood Mononuclear Cell Oxytocin and Vasopressin Receptor Expression Positively Correlates Received: 13 June 2019 Accepted: 28 August 2019 with Social and Behavioral Function Published: xx xx xxxx in Children with Autism Irena Voinsky 1, Sirish C. Bennuri2, Julie Svigals1, Richard E. Frye 3,4, Shannon Rose 2 & David Gurwitz 1,5 The peptide hormone oxytocin is an established regulator of social function in mammals, and dysregulated oxytocin signaling is implicated in autism spectrum disorder (ASD). Several clinical trials examining the efects of intranasal oxytocin for improving social and behavioral function in ASD have had mixed or inclusive outcomes. The heterogeneity in clinical trials outcomes may refect large inter- individual expression variations of the oxytocin and/or vasopressin receptor genes OXTR and AVPR1A, respectively. To explore this hypothesis we examined the expression of both genes in peripheral blood mononuclear cells (PBMC) from ASD children, their non-ASD siblings, and age-matched neurotypical children aged 3 to 16 years of age as well as datamined published ASD datasets. Both genes were found to have large inter-individual variations. Higher OXTR and AVPR1A expression was associated with lower Aberrant Behavior Checklist (ABC) scores. OXTR expression was associated with less severe behavior and higher adaptive behavior on additional standardized measures. Combining the sum expression levels OXTR, AVPR1A, and IGF1 yielded the strongest correlation with ABC scores. We propose that future clinical trials in ASD children with oxytocin, oxytocin mimetics and additional tentative therapeutics should assess the prognostic value of their PBMC mRNA expression of OXTR, AVPR1A, and IGF1.
    [Show full text]
  • G-Protein-Coupled Receptors in CNS: a Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits
    cells Review G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits Shofiul Azam 1 , Md. Ezazul Haque 1, Md. Jakaria 1,2 , Song-Hee Jo 1, In-Su Kim 3,* and Dong-Kug Choi 1,3,* 1 Department of Applied Life Science & Integrated Bioscience, Graduate School, Konkuk University, Chungju 27478, Korea; shofi[email protected] (S.A.); [email protected] (M.E.H.); md.jakaria@florey.edu.au (M.J.); [email protected] (S.-H.J.) 2 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia 3 Department of Integrated Bioscience & Biotechnology, College of Biomedical and Health Science, and Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Korea * Correspondence: [email protected] (I.-S.K.); [email protected] (D.-K.C.); Tel.: +82-010-3876-4773 (I.-S.K.); +82-43-840-3610 (D.-K.C.); Fax: +82-43-840-3872 (D.-K.C.) Received: 16 January 2020; Accepted: 18 February 2020; Published: 23 February 2020 Abstract: Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals.
    [Show full text]