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Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors
G-protein–coupled receptors (GPCRs) are generally thought to signal to second messengers like cyclic AMP (cAMP) from the cell surface and to become internalized upon repeated or prolonged stimulation. Once internalized, they are supposed to stop signaling to second messengers but may trigger nonclas...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718703/ https://www.ncbi.nlm.nih.gov/pubmed/19688034 http://dx.doi.org/10.1371/journal.pbio.1000172 |
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author | Calebiro, Davide Nikolaev, Viacheslav O. Gagliani, Maria Cristina de Filippis, Tiziana Dees, Christian Tacchetti, Carlo Persani, Luca Lohse, Martin J. |
author_facet | Calebiro, Davide Nikolaev, Viacheslav O. Gagliani, Maria Cristina de Filippis, Tiziana Dees, Christian Tacchetti, Carlo Persani, Luca Lohse, Martin J. |
author_sort | Calebiro, Davide |
collection | PubMed |
description | G-protein–coupled receptors (GPCRs) are generally thought to signal to second messengers like cyclic AMP (cAMP) from the cell surface and to become internalized upon repeated or prolonged stimulation. Once internalized, they are supposed to stop signaling to second messengers but may trigger nonclassical signals such as mitogen-activated protein kinase (MAPK) activation. Here, we show that a GPCR continues to stimulate cAMP production in a sustained manner after internalization. We generated transgenic mice with ubiquitous expression of a fluorescent sensor for cAMP and studied cAMP responses to thyroid-stimulating hormone (TSH) in native, 3-D thyroid follicles isolated from these mice. TSH stimulation caused internalization of the TSH receptors into a pre-Golgi compartment in close association with G-protein α(s)-subunits and adenylyl cyclase III. Receptors internalized together with TSH and produced downstream cellular responses that were distinct from those triggered by cell surface receptors. These data suggest that classical paradigms of GPCR signaling may need revision, as they indicate that cAMP signaling by GPCRs may occur both at the cell surface and from intracellular sites, but with different consequences for the cell. |
format | Text |
id | pubmed-2718703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-27187032009-08-18 Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors Calebiro, Davide Nikolaev, Viacheslav O. Gagliani, Maria Cristina de Filippis, Tiziana Dees, Christian Tacchetti, Carlo Persani, Luca Lohse, Martin J. PLoS Biol Research Article G-protein–coupled receptors (GPCRs) are generally thought to signal to second messengers like cyclic AMP (cAMP) from the cell surface and to become internalized upon repeated or prolonged stimulation. Once internalized, they are supposed to stop signaling to second messengers but may trigger nonclassical signals such as mitogen-activated protein kinase (MAPK) activation. Here, we show that a GPCR continues to stimulate cAMP production in a sustained manner after internalization. We generated transgenic mice with ubiquitous expression of a fluorescent sensor for cAMP and studied cAMP responses to thyroid-stimulating hormone (TSH) in native, 3-D thyroid follicles isolated from these mice. TSH stimulation caused internalization of the TSH receptors into a pre-Golgi compartment in close association with G-protein α(s)-subunits and adenylyl cyclase III. Receptors internalized together with TSH and produced downstream cellular responses that were distinct from those triggered by cell surface receptors. These data suggest that classical paradigms of GPCR signaling may need revision, as they indicate that cAMP signaling by GPCRs may occur both at the cell surface and from intracellular sites, but with different consequences for the cell. Public Library of Science 2009-08-18 /pmc/articles/PMC2718703/ /pubmed/19688034 http://dx.doi.org/10.1371/journal.pbio.1000172 Text en Calebiro 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 Calebiro, Davide Nikolaev, Viacheslav O. Gagliani, Maria Cristina de Filippis, Tiziana Dees, Christian Tacchetti, Carlo Persani, Luca Lohse, Martin J. Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors |
title | Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors |
title_full | Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors |
title_fullStr | Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors |
title_full_unstemmed | Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors |
title_short | Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors |
title_sort | persistent camp-signals triggered by internalized g-protein–coupled receptors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718703/ https://www.ncbi.nlm.nih.gov/pubmed/19688034 http://dx.doi.org/10.1371/journal.pbio.1000172 |
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