Persistent cAMP-signals triggered by internalized G-protein-coupled
receptors
D. Calebiro, V. Nikolaev, M. Gagliani, T. de Filippis, C. Dees, C. Tacchetti, L. Persani, and M. Lohse. PLoS Biol, 7 (8):
e1000172(August 2009)Calebiro, Davide Nikolaev, Viacheslav O Gagliani, Maria Cristina
de Filippis, Tiziana Dees, Christian Tacchetti, Carlo Persani, Luca
Lohse, Martin J Research Support, Non-U.S. Gov't United States PLoS
biology PLoS Biol. 2009 Aug;7(8):e1000172. Epub 2009 Aug 18..
Abstract
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.
Calebiro, Davide Nikolaev, Viacheslav O Gagliani, Maria Cristina
de Filippis, Tiziana Dees, Christian Tacchetti, Carlo Persani, Luca
Lohse, Martin J Research Support, Non-U.S. Gov't United States PLoS
biology PLoS Biol. 2009 Aug;7(8):e1000172. Epub 2009 Aug 18.
%0 Journal Article
%1 Calebiro2009
%A Calebiro, D.
%A Nikolaev, V. O.
%A Gagliani, M. C.
%A de Filippis, T.
%A Dees, C.
%A Tacchetti, C.
%A Persani, L.
%A Lohse, M. J.
%D 2009
%J PLoS Biol
%K *Signal AMP/*metabolism Adenylate Animals Biological Cell Cells/cytology/metabolism/ultrastructure Chemicals/metabolism Confocal Cultured Cyclase/genetics/metabolism Cyclic Dyes/metabolism Epithelial Fluorescent Fractions/*metabolism GTP-Binding Gland/cytology/*metabolism Humans Line Mice Microscopy, Models, Organic Protein Subcellular Subunits/*metabolism Thyroid Thyrotropin/*metabolism/pharmacology Thyrotropin/metabolism Transduction Transgenic alpha Receptor
%N 8
%P e1000172
%T Persistent cAMP-signals triggered by internalized G-protein-coupled
receptors
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19688034
%V 7
%X 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.
@article{Calebiro2009,
abstract = {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.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Calebiro, D. and Nikolaev, V. O. and Gagliani, M. C. and de Filippis, T. and Dees, C. and Tacchetti, C. and Persani, L. and Lohse, M. J.},
biburl = {https://www.bibsonomy.org/bibtex/24167de59da2705981290e92a01ce40b6/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {128e5b30e8ecf97bf6a7f8a8432f0fed},
intrahash = {4167de59da2705981290e92a01ce40b6},
issn = {1545-7885 (Electronic) 1545-7885 (Linking)},
journal = {PLoS Biol},
keywords = {*Signal AMP/*metabolism Adenylate Animals Biological Cell Cells/cytology/metabolism/ultrastructure Chemicals/metabolism Confocal Cultured Cyclase/genetics/metabolism Cyclic Dyes/metabolism Epithelial Fluorescent Fractions/*metabolism GTP-Binding Gland/cytology/*metabolism Humans Line Mice Microscopy, Models, Organic Protein Subcellular Subunits/*metabolism Thyroid Thyrotropin/*metabolism/pharmacology Thyrotropin/metabolism Transduction Transgenic alpha Receptor},
month = Aug,
note = {Calebiro, Davide Nikolaev, Viacheslav O Gagliani, Maria Cristina
de Filippis, Tiziana Dees, Christian Tacchetti, Carlo Persani, Luca
Lohse, Martin J Research Support, Non-U.S. Gov't United States PLoS
biology PLoS Biol. 2009 Aug;7(8):e1000172. Epub 2009 Aug 18.},
number = 8,
pages = {e1000172},
shorttitle = {Persistent cAMP-signals triggered by internalized G-protein-coupled
receptors},
timestamp = {2010-12-14T18:21:24.000+0100},
title = {Persistent cAMP-signals triggered by internalized G-protein-coupled
receptors},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19688034},
volume = 7,
year = 2009
}