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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
Author to whom correspondence should be addressed.
Academic Editor: Yung Hou Wong
Molecules 2017, 22(1), 22;
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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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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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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