Functional Consequences of Glucagon-like Peptide-1 Receptor Cross-talk and Trafficking
| Autor: | Sanne Moeller Knudsen, Pernille Wismann, Maria Waldhoer, Sarah Norklit Roed, Helle Iversen, Anne Cathrine Nøhr, Hans Bräuner-Osborne |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
endocrine system
media_common.quotation_subject education Incretin Gastric Inhibitory Polypeptide Biology Ligands environment and public health Incretins Biochemistry Glucagon-Like Peptide-1 Receptor Receptors G-Protein-Coupled Islets of Langerhans Receptors Glucagon medicine Humans Receptor Internalization Molecular Biology Dynamin I media_common G protein-coupled receptor Dynamin Pancreatic islets digestive oral and skin physiology Cell Biology Glucagon Cell biology Protein Transport HEK293 Cells medicine.anatomical_structure Diabetes Mellitus Type 2 Gene Expression Regulation Receptor Cross-Talk biological phenomena cell phenomena and immunity Signal transduction hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 290:1233-1243 |
| ISSN: | 0021-9258 |
| Popis: | The signaling capacity of seven-transmembrane/G-protein-coupled receptors (7TM/GPCRs) can be regulated through ligand-mediated receptor trafficking. Classically, the recycling of internalized receptors is associated with resensitization, whereas receptor degradation terminates signaling. We have shown previously that the incretin glucagon-like peptide-1 receptor (GLP-1R) internalizes fast and is primarily resensitized through recycling back to the cell surface. GLP-1R is expressed in pancreatic islets together with the closely related glucose-dependent insulinotropic polypeptide (GIPR) and glucagon (GCGR) receptors. The interaction and cross-talk between coexpressed receptors is a wide phenomenon of the 7TM/GPCR superfamily. Numerous reports show functional consequences for signaling and trafficking of the involved receptors. On the basis of the high structural similarity and tissue coexpression, we here investigated the potential cross-talk between GLP-1R and GIPR or GCGR in both trafficking and signaling pathways. Using a real-time time-resolved FRET-based internalization assay, we show that GLP-1R, GIPR, and GCGR internalize with differential properties. Remarkably, upon coexpression of the internalizing GLP-1R and the non-internalizing GIPR, GLP-1-mediated GLP-1R internalization was impaired in a GIPR concentration-dependent manner. As a functional consequence of such impaired internalization capability, GLP-1-mediated GLP-1R signaling was abrogated. A similar compromised signaling was found when GLP-1R internalization was abrogated by a dominant-negative version of dynamin (dynamin-1 K44E), which provides a mechanistic link between GLP-1R trafficking and signaling. This study highlights the importance of receptor internalization for full functionality of GLP-1R. Moreover, cross-talk between the two incretin receptors GLP-1R and GIPR is shown to alter receptor trafficking with functional consequences for GLP-1R signaling. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|