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The Ubiquitination Status of the Glucagon Receptor determines Signal Bias.

The pancreatic hormone glucagon activates the glucagon receptor (GCGR), a class B seven-transmembrane G protein-coupled receptor (GPCR) that couples to the stimulatory heterotrimeric Gs protein and provokes protein kinase A-dependent signaling cascades vital to hepatic glucose metabolism and islet insulin secretion. Glucagon-stimulation also initiates recruitment of the endocytic adaptors, β-arrestin1 and β-arrestin2, which regulate desensitization and internalization of the GCGR. Unlike many other GPCRs, the GCGR expressed at the plasma membrane is constitutively ubiquitinated and upon agonist-activation, internalized GCGRs are deubiquitinated at early endosomes and recycled via Rab4-containing vesicles. Herein we report a novel link between the ubiquitination status and signal transduction mechanism of the GCGR. In the deubiquitinated state, coupling of the GCGR to Gs is diminished, while binding to β-arrestin is enhanced with signaling biased to a β-arrestin1-dependent p38 mitogen activated protein kinase (MAPK) pathway. This ubiquitin-dependent signaling bias arises through the modification of lysine333 (K333) on the cytoplasmic face of transmembrane helix V. Compared with the GCGR-WT, the mutant GCGR-K333R has impaired ubiquitination, diminished G protein coupling and protein kinase A signaling, but unimpaired potentiation of glucose-stimulated-insulin secretion in response to agonist-stimulation, which involves p38 MAPK signaling. Both WT and GCGR-K333R promote the formation of glucagon-induced β-arrestin1-dependent p38 signaling scaffold that requires canonical upstream MAPK-Kinase3, but is independent of Gs, Gi and β-arrestin2. Thus ubiquitination/deubiquitination at K333 in the GCGR defines the activation of distinct transducers with the potential to influence various facets of glucagon signaling in health and disease.

Date de publication
8 avril 2023
Kaur S, Sokrat B, Capozzi ME, El K, Bai Y, Jazic A, Han B, Krishnakumar K, D'Alessio DA, Campbell JE, Bouvier M, Shenoy SK
Référence PubMed
J Biol Chem 2023:104690
ID PubMed
Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.