Functional Consequences of Glucagon-Like Peptide-1 Receptor Crosstalk and Trafficking [Signal Transduction]

December 1st, 2014 by Roed, S. N., Nohr, A. C., Wismann, P., Iversen, H., Brauner–Osborne, H., Knudsen, S. M., Waldhoer, M.

The signaling capacity of the 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, whilst receptor degradation terminates signaling. We have previously shown 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 the pancreatic islets together with the closely related glucose-dependent insulinotropic polypeptide- (GIPR) and glucagon receptors (GCGR). The interaction and crosstalk between co-expressed receptors is a wide phenomenon of the 7TM/GPCR superfamily. Numerous reports show functional consequences for signaling and trafficking of the involved receptors. Based on the high structural similarity and tissue co-expression, we here investigated the potential crosstalk between GLP-1R and GIPR or GCGR on both trafficking and signaling pathways. Using a real-time TR-FRET based internalization assay we show that GLP-1R, GIPR and GCGR internalize with differential properties. Remarkably, upon co-expression of the internalizing GLP-1R and the non-internalizing GIPR, the 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 the internalization of the GLP-1R was abrogated by a dominant negative version of dynamin (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, crosstalk between the two incretin receptors GLP-1R and GIPR is shown to alter receptor trafficking with functional consequences for GLP-1R signaling.