Downregulation of a GPCR by β-Arrestin2-Mediated Switch from an Endosomal to a TGN Recycling Pathway

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Nazish Abdullah, Muheeb Beg, David Soares, Jeremy S. Dittman, Timothy E. McGraw
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in nutrient homeostasis. GIP receptor (GIPR) is constitutively internalized and returned to the plasma membrane, atypical behavior for a G-protein-coupled receptor (GPCR). GIP promotes GIPR downregulation from the plasma membrane by inhibiting recycling without affecting internalization. This transient desensitization is achieved by altered intracellular trafficking of activated GIPR. GIP stimulation induces a switch in GIPR recycling from a rapid endosomal to a slow trans-Golgi network (TGN) pathway. GPCR kinases and β-arrestin2 are required for this switch in recycling. A coding sequence variant of GIPR, which has been associated with metabolic alterations, has altered post-activation trafficking characterized by enhanced downregulation and prolonged desensitization. Downregulation of the variant requires β-arrestin2 targeting to the TGN but is independent of GPCR kinases. The single amino acid substitution in the variant biases the receptor to promote GIP-stimulated β-arrestin2 recruitment without receptor phosphorylation, thereby enhancing downregulation.

Graphical abstract

Teaser

Constitutive GIPR recycling is reduced upon GIP stimulation, leading to downregulation of the receptor. Abdullah et al. find that β-arrestin2-mediated trafficking of GIPR to the TGN underlies this slow recycling. Dysregulation of phosphorylation-dependent β-arrestin2 recruitment in a natural coding variant leads to enhanced downregulation.


http://ift.tt/2gZAA30