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Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation

Aiysha Thompson, Venkat Kanamarlapudi Orcid Logo

Molecular and Cellular Endocrinology, Volume: 413, Pages: 66 - 77

Swansea University Author: Venkat Kanamarlapudi Orcid Logo

DOI (Published version): 10.1016/j.mce.2015.06.012

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 involve...

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Published in: Molecular and Cellular Endocrinology
Published: 2015
URI: https://cronfa.swan.ac.uk/Record/cronfa22217
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first_indexed 2015-06-30T02:08:27Z
last_indexed 2019-08-28T19:43:38Z
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spelling 2019-08-28T14:23:11.7159116 v2 22217 2015-06-29 Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 2015-06-29 BMS 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. Journal Article Molecular and Cellular Endocrinology 413 66 77 Glucagon like peptide-1 (GLP-1); GLP-1 receptor (GLP-1R); G protein coupled receptor (GPCR); Biosynthetic trafficking; C-terminus; Diabetes 24 6 2015 2015-06-24 10.1016/j.mce.2015.06.012 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-08-28T14:23:11.7159116 2015-06-29T14:58:27.1275634 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Aiysha Thompson 1 Venkat Kanamarlapudi 0000-0002-8739-1483 2 0022217-19022016144633.pdf ThompsonDistinctRegionsInTheCTerminus2015AM.pdf 2016-02-19T14:46:33.1100000 Output 1694779 application/pdf Accepted Manuscript true 2016-06-24T00:00:00.0000000 true
title Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation
spellingShingle Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation
Venkat Kanamarlapudi
title_short Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation
title_full Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation
title_fullStr Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation
title_full_unstemmed Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation
title_sort Distinct Regions in the C-Terminus Required for GLP-1R Cell Surface Expression, Activity and Internalisation
author_id_str_mv 63741801137148abfa4c00cd547dcdfa
author_id_fullname_str_mv 63741801137148abfa4c00cd547dcdfa_***_Venkat Kanamarlapudi
author Venkat Kanamarlapudi
author2 Aiysha Thompson
Venkat Kanamarlapudi
format Journal article
container_title Molecular and Cellular Endocrinology
container_volume 413
container_start_page 66
publishDate 2015
institution Swansea University
doi_str_mv 10.1016/j.mce.2015.06.012
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.
published_date 2015-06-24T03:26:26Z
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score 11.01628

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