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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,...

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Autores principales: Andreassen, Kim Vietz, Hjuler, Sara Toftegaard, Furness, Sebastian G., Sexton, Patrick M., Christopoulos, Arthur, Nosjean, Olivier, Karsdal, Morten Asser, Henriksen, Kim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
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.
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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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