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Molecules 2017, 22(1), 22; doi:10.3390/molecules22010022

Rate of Homologous Desensitization and Internalization of the GLP-1 Receptor

Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait
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Author to whom correspondence should be addressed.
Academic Editor: Yung Hou Wong
Received: 23 November 2016 / Revised: 13 December 2016 / Accepted: 22 December 2016 / Published: 26 December 2016
(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)
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Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is an important target in the treatment of type 2 diabetes mellitus. The aim of this study was to compare the rate of agonist stimulated desensitization and internalization of GLP-1R. To this end, an N-terminally myc-tagged GLP-1R was stably expressed in HEK-293 cells. Homologous desensitization was assessed by measuring the cAMP response to agonist stimulation following pre-incubation with agonist for up to 120 min. Receptor internalization was monitored using an indirect ELISA-based method and confocal microscopy. Pre-incubation with GLP-1 resulted in a time-dependent loss of response to a second stimulation. Washing cells following pre-incubation failed to bring cAMP levels back to basal. Taking this into account, two desensitization rates were calculated: “apparent” (t1/2 = 19.27 min) and “net” (t1/2 = 2.99 min). Incubation of cells with GLP-1 also resulted in a time-dependent loss of receptor cell surface expression (t1/2 = 2.05 min). Rapid agonist-stimulated internalization of GLP-1R was confirmed using confocal microscopy. Stimulation of GLP-1R with GLP-1 results in rapid desensitization and internalization of the receptor. Interestingly, the rate of “net” desensitization closely matches the rate of internalization. Our results suggest that agonist-bound GLP-1R continues to generate cAMP after it has been internalized. View Full-Text
Keywords: GLP-1; receptor; desensitization; internalization GLP-1; receptor; desensitization; internalization
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Shaaban, G.; Oriowo, M.; Al-Sabah, S. Rate of Homologous Desensitization and Internalization of the GLP-1 Receptor. Molecules 2017, 22, 22.

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