Persistent cAMP-signals triggered by internalized G-protein-coupled receptors

Davide Calebiro, Viacheslav O. Nikolaev, Maria Cristina Gagliani, Tiziana De Filippis, Christian Dees, Carlo Tacchetti, Luca Persani, Martin J. Lohse

Research output: Contribution to journalArticle

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 αs- 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.

Original languageEnglish
Article numbere1000172
JournalPLoS Biology
Volume7
Issue number8
DOIs
Publication statusPublished - Aug 2009

Fingerprint

cyclic AMP
G-Protein-Coupled Receptors
Cyclic AMP
thyrotropin
Thyrotropin
second messengers
Second Messenger Systems
cells
Thyrotropin Receptors
receptors
adenylate cyclase
mice
Protein Subunits
Cell Surface Receptors
Mitogen-Activated Protein Kinases
G-proteins
mitogen-activated protein kinase
GTP-Binding Proteins
Transgenic Mice
Thyroid Gland

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Calebiro, D., Nikolaev, V. O., Gagliani, M. C., De Filippis, T., Dees, C., Tacchetti, C., ... Lohse, M. J. (2009). Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biology, 7(8), [e1000172]. https://doi.org/10.1371/journal.pbio.1000172

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.

In: PLoS Biology, Vol. 7, No. 8, e1000172, 08.2009.

Research output: Contribution to journalArticle

Calebiro, D, Nikolaev, VO, Gagliani, MC, De Filippis, T, Dees, C, Tacchetti, C, Persani, L & Lohse, MJ 2009, 'Persistent cAMP-signals triggered by internalized G-protein-coupled receptors', PLoS Biology, vol. 7, no. 8, e1000172. https://doi.org/10.1371/journal.pbio.1000172
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. In: PLoS Biology. 2009 ; Vol. 7, No. 8.
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