Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias
Identifieur interne : 002A02 ( Pmc/Curation ); précédent : 002A01; suivant : 002A03Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias
Auteurs : Kim Vietz Andreassen [Danemark] ; Sara Toftegaard Hjuler [Danemark] ; Sebastian G. Furness [Australie] ; Patrick M. Sexton [Australie] ; Arthur Christopoulos [Australie] ; Olivier Nosjean [France] ; Morten Asser Karsdal [Danemark] ; Kim Henriksen [Danemark]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
Abstract
Salmon calcitonin (sCT) and human calcitonin (hCT) are pharmacologically distinct. However, the reason for the differences is unclear. Here we analyze the differences between sCT and hCT on the human calcitonin receptor (CT(a)R) with respect to activation of cAMP signaling, β-arrestin recruitment, ligand binding kinetics and internalization. The study was conducted using mammalian cell lines heterologously expressing the human CT(a) receptor. CT(a)R downstream signaling was investigated with dose response profiles for cAMP production and β-arrestin recruitment for sCT and hCT during short term (<2 hours) and prolonged (up to 72 hours) stimulation. CT(a)R kinetics and internalization was investigated with radio-labeled sCT and hCT ligands on cultured cells and isolated membrane preparations from the same cell line. We found that sCT and hCT are equipotent during short-term stimulations with differences manifesting themselves only during long-term stimulation with sCT inducing a prolonged activation up to 72 hours, while hCT loses activity markedly earlier. The prolonged sCT stimulation of both cAMP accumulation and β-arrestin recruitment was attenuated, but not abrogated by acid wash, suggesting a role for sCT activated internalized receptors. We have demonstrated a novel phenomenon, namely that two distinct CT(a)R downstream signaling activation patterns are activated by two related ligands, thereby highlighting qualitatively different signaling responses in vitro that could have implications for sCT use in vivo.
Url:
DOI: 10.1371/journal.pone.0092042
PubMed: 24643196
PubMed Central: 3958426
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Furness</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria</wicri:regionArea></affiliation></author><author><name sortKey="Sexton, Patrick M" sort="Sexton, Patrick M" uniqKey="Sexton P" first="Patrick M." last="Sexton">Patrick M. Sexton</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria</wicri:regionArea></affiliation></author><author><name sortKey="Christopoulos, Arthur" sort="Christopoulos, Arthur" uniqKey="Christopoulos A" first="Arthur" last="Christopoulos">Arthur Christopoulos</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria</wicri:regionArea></affiliation></author><author><name sortKey="Nosjean, Olivier" sort="Nosjean, Olivier" uniqKey="Nosjean O" first="Olivier" last="Nosjean">Olivier Nosjean</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut de Recherches Servier, Croissy-sur-Seine, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Recherches Servier, Croissy-sur-Seine</wicri:regionArea></affiliation></author><author><name sortKey="Karsdal, Morten Asser" sort="Karsdal, Morten Asser" uniqKey="Karsdal M" first="Morten Asser" last="Karsdal">Morten Asser Karsdal</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Nordic Bioscience A/S, Herlev, Denmark</addr-line></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Nordic Bioscience A/S, Herlev</wicri:regionArea></affiliation></author><author><name sortKey="Henriksen, Kim" sort="Henriksen, Kim" uniqKey="Henriksen K" first="Kim" last="Henriksen">Kim Henriksen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Nordic Bioscience A/S, Herlev, Denmark</addr-line></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Nordic Bioscience A/S, Herlev</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Salmon calcitonin (sCT) and human calcitonin (hCT) are pharmacologically distinct. However, the reason for the differences is unclear. Here we analyze the differences between sCT and hCT on the human calcitonin receptor (CT<sub>(a)</sub>R) with respect to activation of cAMP signaling, β-arrestin recruitment, ligand binding kinetics and internalization. The study was conducted using mammalian cell lines heterologously expressing the human CT<sub>(a)</sub> receptor. CT<sub>(a)</sub>R downstream signaling was investigated with dose response profiles for cAMP production and β-arrestin recruitment for sCT and hCT during short term (<2 hours) and prolonged (up to 72 hours) stimulation. CT<sub>(a)</sub>R kinetics and internalization was investigated with radio-labeled sCT and hCT ligands on cultured cells and isolated membrane preparations from the same cell line. We found that sCT and hCT are equipotent during short-term stimulations with differences manifesting themselves only during long-term stimulation with sCT inducing a prolonged activation up to 72 hours, while hCT loses activity markedly earlier. The prolonged sCT stimulation of both cAMP accumulation and β-arrestin recruitment was attenuated, but not abrogated by acid wash, suggesting a role for sCT activated internalized receptors. We have demonstrated a novel phenomenon, namely that two distinct CT<sub>(a)</sub>R downstream signaling activation patterns are activated by two related ligands, thereby highlighting qualitatively different signaling responses in vitro that could have implications for sCT use in vivo.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Pham, Vi" uniqKey="Pham V">VI Pham</name></author><author><name sortKey="Sexton, Pm" uniqKey="Sexton P">PM Sexton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Poyner, Dr" uniqKey="Poyner D">DR Poyner</name></author><author><name sortKey="Sexton, Pm" uniqKey="Sexton P">PM Sexton</name></author><author><name sortKey="Marshall, I" uniqKey="Marshall I">I Marshall</name></author><author><name sortKey="Smith, Dm" uniqKey="Smith D">DM Smith</name></author><author><name sortKey="Quirion, R" uniqKey="Quirion R">R 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Symonds</name></author><author><name sortKey="Darby, Ja" uniqKey="Darby J">JA Darby</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24643196</article-id><article-id pub-id-type="pmc">3958426</article-id><article-id pub-id-type="publisher-id">PONE-D-13-41545</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0092042</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Computer and Information Sciences</subject><subj-group><subject>Network Analysis</subject><subj-group><subject>Signaling Networks</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Cell Signaling</subject><subj-group><subject>Membrane Receptor Signaling</subject><subj-group><subject>Hormone Receptor Signaling</subject></subj-group></subj-group><subj-group><subject>Signaling Cascades</subject></subj-group></subj-group><subj-group><subject>Mechanisms of Signal Transduction</subject><subj-group><subject>Second Messenger System</subject></subj-group></subj-group></subj-group><subj-group><subject>Molecular Cell Biology</subject></subj-group></subj-group><subj-group><subject>Biochemistry</subject><subj-group><subject>Enzymology</subject><subj-group><subject>Enzymes</subject><subj-group><subject>Lyases</subject><subj-group><subject>Adenylyl Cyclase</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group><subject>Computational Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias</article-title><alt-title alt-title-type="running-head">sCT, but Not hCT Causes Prolonged CTR Signaling</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Andreassen</surname><given-names>Kim Vietz</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hjuler</surname><given-names>Sara Toftegaard</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Furness</surname><given-names>Sebastian G.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sexton</surname><given-names>Patrick M.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Christopoulos</surname><given-names>Arthur</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nosjean</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Karsdal</surname><given-names>Morten Asser</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Henriksen</surname><given-names>Kim</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Nordic Bioscience A/S, Herlev, Denmark</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Institut de Recherches Servier, Croissy-sur-Seine, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Seifert</surname><given-names>Roland</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Medical School of Hannover, Germany</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>kan@nordicbioscience.com</email></corresp><fn fn-type="conflict"><p><bold>Competing Interests: </bold>Kim Vietz Andreassen, Sara Toftegaard Hjuler, Morten Asser Karsdal and Kim Henriksen are employed by Nordic Bioscience A/S. Morten Asser Karsdal own stock in Nordic Bioscience Olivier Nosjean is an employee of Institut de Recherches Servier. All other authors have no conflicts of interest This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: KVA STH SGF PMS AC ON MAK KH. Performed the experiments: KVA STH. Analyzed the data: KVA STH SGF PMS AC ON MAK KH. Contributed reagents/materials/analysis tools: SGF PMS AC ON MAK KH. Wrote the paper: KVA STH SGF PMS AC ON MAK KH.</p></fn></author-notes><pub-date pub-type="collection"><year>2014</year></pub-date><pub-date pub-type="epub"><day>18</day><month>3</month><year>2014</year></pub-date><volume>9</volume><issue>3</issue><elocation-id>e92042</elocation-id><history><date date-type="received"><day>11</day><month>10</month><year>2013</year></date><date date-type="accepted"><day>19</day><month>2</month><year>2014</year></date></history><permissions><copyright-year>2014</copyright-year><copyright-holder>Andreassen et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Salmon calcitonin (sCT) and human calcitonin (hCT) are pharmacologically distinct. However, the reason for the differences is unclear. Here we analyze the differences between sCT and hCT on the human calcitonin receptor (CT<sub>(a)</sub>R) with respect to activation of cAMP signaling, β-arrestin recruitment, ligand binding kinetics and internalization. The study was conducted using mammalian cell lines heterologously expressing the human CT<sub>(a)</sub> receptor. CT<sub>(a)</sub>R downstream signaling was investigated with dose response profiles for cAMP production and β-arrestin recruitment for sCT and hCT during short term (<2 hours) and prolonged (up to 72 hours) stimulation. CT<sub>(a)</sub>R kinetics and internalization was investigated with radio-labeled sCT and hCT ligands on cultured cells and isolated membrane preparations from the same cell line. We found that sCT and hCT are equipotent during short-term stimulations with differences manifesting themselves only during long-term stimulation with sCT inducing a prolonged activation up to 72 hours, while hCT loses activity markedly earlier. The prolonged sCT stimulation of both cAMP accumulation and β-arrestin recruitment was attenuated, but not abrogated by acid wash, suggesting a role for sCT activated internalized receptors. We have demonstrated a novel phenomenon, namely that two distinct CT<sub>(a)</sub>R downstream signaling activation patterns are activated by two related ligands, thereby highlighting qualitatively different signaling responses in vitro that could have implications for sCT use in vivo.</p></abstract><funding-group><funding-statement>Partly funded by Danish Research Foundation and the Danish Ministry for Science, Technology and Education. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="10"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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