Signal Transduction
Functional Consequences of Glucagon-like Peptide-1 Receptor Cross-talk and Trafficking*

https://doi.org/10.1074/jbc.M114.592436Get rights and content
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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.Receptor trafficking and cross-talk regulate 7TM/GPCR signaling capacity.

Results

Inhibition of GLP-1R internalization in the presence of GIPR reduces GLP-1R signaling.

Conclusion

GLP-1R internalization is essential for full receptor functionality and is abrogated upon cross-talk with GIPR.

Significance

GLP-1R cross-talk with GIPR has functional consequences for GLP-1R signaling.

Fluorescence Resonance Energy Transfer (FRET)
G-protein-coupled Receptor (GPCR)
Intracellular Trafficking
Receptor Internalization
Signal Transduction
Type 2 Diabetes
Glucagon-like Peptide-1
Glucose-dependent Insulinotropic Polypeptide
Receptor Cross-talk
Seven Transmembrane-spanning Receptor

Cited by (0)

*

Sarah Noerklit Roed and Sanne Moeller Knudsen own Novo Nordisk A/S stocks.

2

Supported by the Carlsberg Foundation.