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Q Xiao, W Jeng, and MB Wheeler

Glucagon-like peptide 1 (GLP-1) is a potent insulinotropic hormone currently under study as a therapeutic agent for type 2 diabetes. Since an understanding of the molecular mechanisms leading to high-affinity receptor (R) binding and activation may facilitate the development of more potent GLP-1R agonists, we have localized specific regions of GLP-1R required for binding. The purified N-terminal fragment (hereafter referred to as NT) of the GLP-1R produced in either insect (Sf9) or mammalian (COS-7) cells was shown to bind GLP-1. The physical interaction of NT with GLP-1 was first demonstrated by cross-linking ((125)I-GLP-1/NT complex band at approximately 28 kDa) and secondly by attachment to Ni(2+)-NTA beads. The GLP-1R NT protein attached to beads bound GLP-1, but with lower affinity (inhibitory concentration (IC(50)): 4.5 x 10(-7) M) than wild-type (WT) GLP-1R (IC(50): 5.2 x 10(-9)M). The low affinity of GLP-1R NT suggested that other receptor domains may contribute to GLP-1 binding. This was supported by studies using chimeric glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptors. GIP(1-151)/GLP-1R, but not GIP(1-222)/GLP-1R, exhibited specific GLP-1 binding and GLP-1-induced cAMP production, suggesting that the region encompassing transmembrane (TM) domain 1 through to TM3 was required for binding. Since it was hypothesized that certain charged or polar amino acids in this region might be involved in binding, these residues (TM2-TM3) were analyzed by substitution mutagenesis. Five mutants (K197A, D198A, K202A, D215A, R227A) displayed remarkably reduced binding affinity. These studies indicate that the NT domain of the GLP-1R is able to bind GLP-1, but charged residues concentrated at the distal TM2/extracellular loop-1 (EC1) interface (K197, D198, K202) and in EC1 (D215 and R227) probably contribute to the binding determinants of the GLP-1R.

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He-jun Zhao, Xia Jiang, Li-juan Hu, Lei Yang, Lian-dong Deng, Ya-ping Wang, and Zhi-peng Ren

. Clinical Cancer Research 1284 – 1285 . ( ) Koehler JA Drucker DJ 2006 Activation of glucagon-like peptide-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells

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Jianling Xie, Norhan M El Sayed, Cheng Qi, Xuechan Zhao, Claire E Moore, and Terence P Herbert

). T2DM develops when β-cells fail to adequately compensate for the increase in insulin demand. Importantly, exendin-4 ( Parker et al . 1984 , Eng et al . 1992 ), a glucagon-like peptide 1 receptor (GLP1R) agonist developed for the management of T2DM

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Giulia Cantini, Martina Trabucco, Alessandra Di Franco, Edoardo Mannucci, and Michaela Luconi

.21.2.93 ) Monami M Dicembrini I Marchionni N Rotella CM Mannucci E 2012 Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis . Experimental Diabetes Research 672658 . ( ) Müller

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Jong-Ik Hwang, Seongsik Yun, Mi Jin Moon, Cho Rong Park, and Jae Young Seong

glucagon-like peptide-1 receptor involved in ligand binding and receptor activation: modelling the ligand-bound receptor . Molecular Endocrinology 25 1804 – 1818 . ( doi:10.1210/me.2011-1160 ). DaCambra MP Yusta B Sumner-Smith M Crivici A

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Ahmed A Hasan and Berthold Hocher

was able to normalize the renal histopathology in both strains. These results showed that DPP-4 inhibition could have reno-protective effects through glucagon-like peptide-1 receptor (GLP-1R) and also through other substrates such as stromal derived

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Maria Sörhede Winzell and Bo Ahrén

: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes . Lancet 368 1696 – 1705 . Egan JM Bulotta A Hui H Perfetti R 2003 GLP-1 receptor agonists are growth and differentiation factors for pancreatic

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Yingyu Feng, Lei Su, Xing Zhong, Wei Guohong, Haipeng Xiao, Yanbing Li, and Lingling Xiu

and Metabolism 94 1843 – 1852 . ( doi:10.1210/jc.2008-1296 ) Aoyama E Watari I Podyma-Inoue KA Yanagishita M Ono T 2014 Expression of glucagon-like peptide-1 receptor and glucosedependent insulinotropic polypeptide receptor

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Özlem Erdogdu, Linnéa Eriksson, Hua Xu, Åke Sjöholm, Qimin Zhang, and Thomas Nyström

C Goto H Nomiyama T Fujitani Y Hirose T Kawamori R Watada H 2010 Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4 . Diabetes 59

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Franziska Boess, Cristina Bertinetti-Lapatki, Sannah Zoffmann, Catherine George, Thomas Pfister, Adrian Roth, Serene M L Lee, Wolfgang E Thasler, Thomas Singer, and Laura Suter

2010 Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation . Endocrinology 151 1473 – 1486 . ( doi:10.1210/en.2009-1272 ). Brubaker PL Drucker DJ 2004 Minireview