Journal article 1287 views
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway
Biochemical Pharmacology, Volume: 93, Issue: 1, Pages: 72 - 84
Swansea University Author:
Venkat Kanamarlapudi
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DOI (Published version): 10.1016/j.bcp.2014.10.015
Abstract
The glucagon like peptide-1 receptor (GLP-1R) is a G-protein coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Gαs and Gαq coupled pathways to stimulate insulin secretion. The agonist in...
Published in: | Biochemical Pharmacology |
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2015
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URI: | https://cronfa.swan.ac.uk/Record/cronfa19150 |
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2019-06-21T15:14:01.6361580 v2 19150 2014-11-10 Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 2014-11-10 BMS The glucagon like peptide-1 receptor (GLP-1R) is a G-protein coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Gαs and Gαq coupled pathways to stimulate insulin secretion. The agonist induced GLP-1R internalisation has recently been shown to be important for insulin secretion. However, the molecular mechanisms underlying GLP-1R internalisation remain unknown. The aim of this study was to determine the role of GLP-1R downstream signalling pathways in its internalisation. Agonist induced human GLP-1R (hGLP-1R) internalisation and activity were examined using a number of techniques including immunoblotting, ELISA, immunofluorescence, and luciferase assays to determine cAMP production, intracellular Ca2+ accumulation and ERK phosphorylation. Agonist induced hGLP-1R internalisation is dependent on caveolin-1 and dynamin. Inhibition of the Gαq pathway but not the Gαs pathway affected hGLP-1R internalisation. Consistent with this, hGLP-1R mutant T149 M and small molecule agonists (compound 2 and compound B), which activate only the Gαs pathway, failed to induce internalisation of the receptor. Chemical inhibitors of the Gαq pathway, PKC and ERK phosphorylation significantly reduced agonist induced hGLP-1R internalisation. These inhibitors also suppressed agonist induced ERK1/2 phosphorylation demonstrating that the phosphorylated ERK acts downstream of the Gαq pathway in the hGLP-1R internalisation. In summary, agonist induced hGLP-1R internalisation is mediated by the Gαq pathway. The internalised hGLP-1R stimulates insulin secretion from pancreatic β-cells, indicating the importance of GLP-1 internalisation for insulin secretion. Journal Article Biochemical Pharmacology 93 1 72 84 Glucagon like peptide-1 (GLP-1); GLP-1 receptor (GLP-1R); G protein coupled receptor (GPCR); Endocytosis; Gαq pathway 1 1 2015 2015-01-01 10.1016/j.bcp.2014.10.015 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-06-21T15:14:01.6361580 2014-11-10T09:50:19.6985418 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Aiysha Thompson 1 Venkat Kanamarlapudi 0000-0002-8739-1483 2 |
title |
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway |
spellingShingle |
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway Venkat Kanamarlapudi |
title_short |
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway |
title_full |
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway |
title_fullStr |
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway |
title_full_unstemmed |
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway |
title_sort |
Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway |
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 |
Biochemical Pharmacology |
container_volume |
93 |
container_issue |
1 |
container_start_page |
72 |
publishDate |
2015 |
institution |
Swansea University |
doi_str_mv |
10.1016/j.bcp.2014.10.015 |
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 |
0 |
active_str |
0 |
description |
The glucagon like peptide-1 receptor (GLP-1R) is a G-protein coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Gαs and Gαq coupled pathways to stimulate insulin secretion. The agonist induced GLP-1R internalisation has recently been shown to be important for insulin secretion. However, the molecular mechanisms underlying GLP-1R internalisation remain unknown. The aim of this study was to determine the role of GLP-1R downstream signalling pathways in its internalisation. Agonist induced human GLP-1R (hGLP-1R) internalisation and activity were examined using a number of techniques including immunoblotting, ELISA, immunofluorescence, and luciferase assays to determine cAMP production, intracellular Ca2+ accumulation and ERK phosphorylation. Agonist induced hGLP-1R internalisation is dependent on caveolin-1 and dynamin. Inhibition of the Gαq pathway but not the Gαs pathway affected hGLP-1R internalisation. Consistent with this, hGLP-1R mutant T149 M and small molecule agonists (compound 2 and compound B), which activate only the Gαs pathway, failed to induce internalisation of the receptor. Chemical inhibitors of the Gαq pathway, PKC and ERK phosphorylation significantly reduced agonist induced hGLP-1R internalisation. These inhibitors also suppressed agonist induced ERK1/2 phosphorylation demonstrating that the phosphorylated ERK acts downstream of the Gαq pathway in the hGLP-1R internalisation. In summary, agonist induced hGLP-1R internalisation is mediated by the Gαq pathway. The internalised hGLP-1R stimulates insulin secretion from pancreatic β-cells, indicating the importance of GLP-1 internalisation for insulin secretion. |
published_date |
2015-01-01T03:22:27Z |
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1763750704549199872 |
score |
11.021648 |