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Internalized TSH receptors en route to the TGN induce local G\(_{S}\)-protein signaling and gene transcription

Please always quote using this URN: urn:nbn:de:bvb:20-opus-170375
  • A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous Gs-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN. BlockingA new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous Gs-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN. Blocking receptor internalization, inhibiting PKA II/interfering with its Golgi/TGN localization, silencing retromer or disrupting Golgi/TGN organization all impair efficient TSH-dependent cAMP response element binding protein (CREB) phosphorylation. These results suggest that retrograde trafficking to the TGN induces local G\(_{S}\)-protein activation and cAMP/PKA signaling at a critical position near the nucleus, which appears required for efficient CREB phosphorylation and gene transcription. This provides a new mechanism to explain the functional consequences of GPCR signaling at intracellular sites and reveals a critical role for the TGN in GPCR signaling.show moreshow less

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Metadaten
Author: Amod Godbole, Sandra Lyga, Martin J. Lohse, Davide CalebiroORCiD
URN:urn:nbn:de:bvb:20-opus-170375
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Pharmakologie und Toxikologie
Fakultät für Biologie / Rudolf-Virchow-Zentrum
Language:English
Parent Title (English):Nature Communications
Year of Completion:2017
Volume:8
Issue:443
Source:Nature Communications 2017, 8:443. DOI: 10.1038/s41467-017-00357-2
DOI:https://doi.org/10.1038/s41467-017-00357-2
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/28874659
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:G protein-coupled receptors; fluorescence imaging; hormone receptors; trans-Golgi network
Release Date:2019/09/23
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International