Journal
PLOS ONE
Volume 11, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0154229
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Funding
- Biotechnology and Biological Sciences Research Council UK [BB/C515455/2]
- Medical Research Council UK [G0401232]
- Biotechnology and Biological Sciences Research Council UK-Nova Nordisk studentship [BB/F017596/1]
- MRC [G0401232] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1095087, BB/C515455/2] Funding Source: researchfish
- Medical Research Council [G0401232] Funding Source: researchfish
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The glucagon-like peptide receptor (GLP-1R), which is a G-protein coupled receptor (GPCR), signals through both G alpha s and G alpha q coupled pathways and ERK phosphorylation to stimulate insulin secretion. The aim of this study was to determine molecular details of the effect of small molecule agonists, compounds 2 and B, on GLP-1R mediated cAMP production, intracellular Ca2+ accumulation, ERK phosphorylation and its internalisation. In human GLP-1R (hGLP-1R) expressing cells, compounds 2 and B induced cAMP production but caused no intracellular Ca2+ accumulation, ERK phosphorylation or hGLP-1R internalisation. GLP-1 antagonists Ex(9-39) and JANT-4 and the orthosteric binding site mutation (V36A) in hGLP-1R failed to inhibit compounds 2 and B induced cAMP production, confirming that their binding site distinct from the GLP-1 binding site on GLP-1R. However, K334A mutation of hGLP-1R, which affects G alpha(s) coupling, inhibited GLP-1 as well as compounds 2 and B induced cAMP production, indicating that GLP-1, compounds 2 and B binding induce similar conformational changes in the GLP-1R for G alpha(s) coupling. Additionally, compound 2 or B binding to the hGLP-1R had significantly reduced GLP-1 induced intracellular Ca2+ accumulation, ERK phosphorylation and hGLP-1R internalisation. This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B.
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