Downregulation of a GPCR by β-Arrestin2-Mediated Switch from an Endosomal to a TGN Recycling Pathway
| Autor: | Jeremy S. Dittman, Timothy E. McGraw, David Soares, Nazish Abdullah, Muheeb Beg |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Endosome media_common.quotation_subject Incretin Endosomes Gastric Inhibitory Polypeptide Biology Incretins Article General Biochemistry Genetics and Molecular Biology Receptors G-Protein-Coupled Receptors Gastrointestinal Hormone Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation 3T3-L1 Cells Internal medicine medicine Animals Humans Internalization Receptor media_common G protein-coupled receptor Kinase beta-Arrestin 2 Cell biology Protein Transport 030104 developmental biology Endocrinology Arrestin beta 2 hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery trans-Golgi Network |
| Zdroj: | Cell Reports. 17:2966-2978 |
| ISSN: | 2211-1247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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