Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/145775
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dc.contributor.authorFang, Zijianen_US
dc.contributor.authorChen, Shiqianen_US
dc.contributor.authorManchanda, Yusmanen_US
dc.contributor.authorBitsi, Stavroulaen_US
dc.contributor.authorPickford, Philipen_US
dc.contributor.authorDavid, Alessiaen_US
dc.contributor.authorShchepinova, Maria M.en_US
dc.contributor.authorCorrêa, Ivan R., Jr.en_US
dc.contributor.authorHodson, David J.en_US
dc.contributor.authorBroichhagen, Johannesen_US
dc.contributor.authorTate, Edward W.en_US
dc.contributor.authorReimann, Franken_US
dc.contributor.authorSalem, Victoriaen_US
dc.contributor.authorRutter, Guy A.en_US
dc.contributor.authorTan, Triciaen_US
dc.contributor.authorBloom, Stephen R.en_US
dc.contributor.authorTomas, Alejandraen_US
dc.contributor.authorJones, Benen_US
dc.date.accessioned2021-01-07T08:39:26Z-
dc.date.available2021-01-07T08:39:26Z-
dc.date.issued2020-
dc.identifier.citationFang, Z., Chen, S., Manchanda, Y., Bitsi, S., Pickford, P., David, A., . . . Jones, B. (2020). Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells. International Journal of Molecular Sciences, 21(21), 8404-. doi:10.3390/ijms21218404en_US
dc.identifier.issn1661-6596en_US
dc.identifier.urihttps://hdl.handle.net/10356/145775-
dc.description.abstractThe glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.en_US
dc.language.isoenen_US
dc.relation.ispartofInternational Journal of Molecular Sciencesen_US
dc.rights© 2020 The Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).en_US
dc.subjectScience::Biological sciencesen_US
dc.titleLigand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cellsen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.identifier.doi10.3390/ijms21218404-
dc.description.versionPublished versionen_US
dc.identifier.pmid33182425-
dc.identifier.issue21en_US
dc.identifier.volume21en_US
dc.subject.keywordsGlucagon-like Peptide-1en_US
dc.subject.keywordsExendin-4en_US
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