title: Distinct regions in the C-Terminus required for GLP-1R cell surface expression, activity and internalisation.
abstract: The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), an important drug target in the treatment of type 2 diabetes, is a G-protein coupled receptor (GPCR) that mediates insulin secretion by GLP-1. The N-terminus controls GLP-1R biosynthetic trafficking to the cell surface but the C-terminus involvement in that trafficking is unknown. The aim of this study was to identify distinct regions within the C-terminal domain required for human GLP-1R (hGLP-1R) cell surface expression, activity and internalisation using a number of C-terminal deletions and site-directed mutations. The results of this study revealed that the residues 411-418 within the C-terminal domain of the hGLP-1R are critical in targeting the newly synthesised receptor to the plasma membrane. The residues 419-430 are important for cAMP producing activity of the receptor, most likely by coupling to Gαs. However, the residues 431-450 within the C-terminus are essential for agonist-induced hGLP-1R internalisation. In conclusion, these findings demonstrate the hGLP-1R has distinct regions within the C-terminal domain required for its cell surface expression, activity and agonist-induced internalisation.
authors.affiliation: Institute of Life Science 1, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Aiysha
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Institute of Life Science 1, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK. Electronic address: k.venkateswarlu@swansea.ac.uk.
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Kanamarlapudi
mesh_terms: D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000096:biosynthesis* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor
keywords: Biosynthetic trafficking; C-terminus; Diabetes; G protein coupled receptor (GPCR); GLP-1 receptor (GLP-1R); Glucagon like peptide-1 (GLP-1)