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      Distinct regions in the C-Terminus required for GLP-1R cell surface expression, activity and internalisation.

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          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.

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          Author and article information

          Journal
          Mol. Cell. Endocrinol.
          Molecular and cellular endocrinology
          Elsevier BV
          1872-8057
          0303-7207
          Sep 15 2015
          : 413
          Affiliations
          [1 ] Institute of Life Science 1, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
          [2 ] Institute of Life Science 1, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK. Electronic address: k.venkateswarlu@swansea.ac.uk.
          Article
          S0303-7207(15)00322-6
          10.1016/j.mce.2015.06.012
          26116235
          277d2e83-5f8a-437f-9604-d36f549b144b
          History

          Biosynthetic trafficking,C-terminus,Diabetes,G protein coupled receptor (GPCR),GLP-1 receptor (GLP-1R),Glucagon like peptide-1 (GLP-1)

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