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Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias
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,...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958426/ https://www.ncbi.nlm.nih.gov/pubmed/24643196 http://dx.doi.org/10.1371/journal.pone.0092042 |
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author | Andreassen, Kim Vietz Hjuler, Sara Toftegaard Furness, Sebastian G. Sexton, Patrick M. Christopoulos, Arthur Nosjean, Olivier Karsdal, Morten Asser Henriksen, Kim |
author_facet | Andreassen, Kim Vietz Hjuler, Sara Toftegaard Furness, Sebastian G. Sexton, Patrick M. Christopoulos, Arthur Nosjean, Olivier Karsdal, Morten Asser Henriksen, Kim |
author_sort | Andreassen, Kim Vietz |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3958426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39584262014-03-24 Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias Andreassen, Kim Vietz Hjuler, Sara Toftegaard Furness, Sebastian G. Sexton, Patrick M. Christopoulos, Arthur Nosjean, Olivier Karsdal, Morten Asser Henriksen, Kim PLoS One Research Article 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. Public Library of Science 2014-03-18 /pmc/articles/PMC3958426/ /pubmed/24643196 http://dx.doi.org/10.1371/journal.pone.0092042 Text en © 2014 Andreassen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Andreassen, Kim Vietz Hjuler, Sara Toftegaard Furness, Sebastian G. Sexton, Patrick M. Christopoulos, Arthur Nosjean, Olivier Karsdal, Morten Asser Henriksen, Kim Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias |
title | Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias |
title_full | Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias |
title_fullStr | Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias |
title_full_unstemmed | Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias |
title_short | Prolonged Calcitonin Receptor Signaling by Salmon, but Not Human Calcitonin, Reveals Ligand Bias |
title_sort | prolonged calcitonin receptor signaling by salmon, but not human calcitonin, reveals ligand bias |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958426/ https://www.ncbi.nlm.nih.gov/pubmed/24643196 http://dx.doi.org/10.1371/journal.pone.0092042 |
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