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...
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doaj-201a828e2bec40258fe9d600884dddf12021-07-02T10:14:25ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852009-08-0178e100017210.1371/journal.pbio.1000172Persistent cAMP-signals triggered by internalized G-protein-coupled receptors.Davide CalebiroViacheslav O NikolaevMaria Cristina GaglianiTiziana de FilippisChristian DeesCarlo TacchettiLuca PersaniMartin J LohseG-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 alpha(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.http://europepmc.org/articles/PMC2718703?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Davide Calebiro Viacheslav O Nikolaev Maria Cristina Gagliani Tiziana de Filippis Christian Dees Carlo Tacchetti Luca Persani Martin J Lohse |
spellingShingle |
Davide Calebiro Viacheslav O Nikolaev Maria Cristina Gagliani Tiziana de Filippis Christian Dees Carlo Tacchetti Luca Persani Martin J Lohse Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biology |
author_facet |
Davide Calebiro Viacheslav O Nikolaev Maria Cristina Gagliani Tiziana de Filippis Christian Dees Carlo Tacchetti Luca Persani Martin J Lohse |
author_sort |
Davide Calebiro |
title |
Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. |
title_short |
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_sort |
persistent camp-signals triggered by internalized g-protein-coupled receptors. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2009-08-01 |
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 alpha(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. |
url |
http://europepmc.org/articles/PMC2718703?pdf=render |
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