%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 }