1521-0081/68/4/954–1013$25.00 http://dx.doi.org/10.1124/pr.115.011395 PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:954–1013, October 2016 Copyright © 2016 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: RICHARD DEQUAN YE Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes Chris de Graaf, Dan Donnelly, Denise Wootten, Jesper Lau, Patrick M. Sexton, Laurence J. Miller, Jung-Mo Ahn, Jiayu Liao, Madeleine M. Fletcher, Dehua Yang, Alastair J. H. Brown, Caihong Zhou, Jiejie Deng, and Ming-Wei Wang Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (C.d.G.); School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom (D.D.); Drug Discovery Biology Theme and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (D.W., P.M.S., M.M.F.); Protein and Peptide Chemistry, Global Research, Novo Nordisk A/S, Måløv, Denmark (J.La.); Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (L.J.M.); Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas (J.-M.A.); Department of Bioengineering, Bourns College of Engineering, University of California at Riverside, Riverside, California (J.Li.); National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (D.Y., C.Z., J.D., M.-W.W.); Heptares Therapeutics, BioPark, Welwyn Garden City, United Kingdom (A.J.H.B.); and School of Pharmacy, Fudan University, Zhangjiang High-Tech Park, Shanghai, China (M.-W.W.) Downloaded from Abstract. ................................................................................... 956 I. Introduction. ............................................................................. 956 II. Glucagon-Like Peptide-1. ................................................................. 957 A. Discovery. ............................................................................. 957 B. Physiology. ............................................................................. 957 by guest on September 27, 2021 1. Effect on Glucose Homeostasis. ..................................................... 958 2. Effect on Gastric Emptying. ......................................................... 958 3. Effect on Food Intake. ............................................................... 959 4. Effect on Cardiovascular Activity..................................................... 959 5. Effect on Immune Response.......................................................... 959 6. Effect on Kidney Function. .......................................................... 960 7. Effect on Nervous System............................................................ 960 C. Structure. ............................................................................. 960 1. a-Helical C-Terminal Region. ..................................................... 962 2. Flexible N-Terminal Region. ......................................................... 962 3. Interaction between the C-Terminal Helix and ECD. .............................. 963 4. Interaction between Flexible N terminus and 7TMD.. .............................. 964 D. Mutagenesis............................................................................ 964 1. Truncated GLP-1 Analogs............................................................ 964 2. Chimeric GLP-1 Analogs. ........................................................... 965 3. Substituted GLP-1 Analogs. ......................................................... 965 a. GLP-1 hydrophobic region I.. ..................................................... 965 b. GLP-1 hydrophobic region II...................................................... 966 c. Polar residues in a-helix.......................................................... 966 d. N-capping motif in GLP-1. ..................................................... 966 This work was supported by National Health and Family Planning Commission of China [2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, and 2013ZX09507-002 to M.-W.W.]; Chinese Academy of Sciences [to M.-W.W.]; Shanghai Science and Technology Development Fund [15DZ2291600 to M.-W.W.]; Thousand Talents Program in China [to M.-W.W.]; the CAS-Novo Nordisk Research Fund [to D.Y.]; National Natural Science Foundation of China [81373463 to D.Y.]; National Health and Medical Research Council of Australia (NHMRC) Principal Research Fellowship [to P.M.S.]; NHMRC Program [Grant 1055134 to P.M.S.]; NHMRC Career Development Fellowship [to D.W.]; NHMRC Project [Grant 1061044 to P.M.S. and Grant 1065410 to D.W.]; Welch Foundation [AT-1595 to J.-M.A.]; and Juvenile Diabetes Research Foundation [37-2011-20 to J.-M.A.]. C.d.G., D.D., and D.W. contributed equally to this work. Address correspondence to: Dr. Ming-Wei Wang, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China. E-mail: [email protected] dx.doi.org/10.1124/pr.115.011395. 954 Glucagon-Like Peptide-1 and Its Receptors 955 e. N terminus of GLP-1. ........................................................... 966 III. Glucagon-Like Peptide 1 Receptor .......................................................... 967 A. Discovery. ............................................................................. 967 1. Receptor Cloning. ................................................................. 967 2. Receptor Expression. ................................................................ 967 3. Receptor Biosynthesis................................................................ 967 B. Structure. ............................................................................. 968 1. N-Terminal Domain. ................................................................ 969 a. Structure determination of the N-terminal ECD................................... 969 b. Site-directed mutagenesis of the ECD. ......................................... 969 2. Seven-Transmembrane Domain. ..................................................... 969 a. Structure of the 7TMD. .......................................................... 969 b. Mutagenesis of the 7TMD. ..................................................... 976 i. TM1 (S1291.24b-L1671.62b).................................................... 976 ii. ICL1 (G168-C174). .......................................................... 976 iii. TM2 (T1752.45b-L2012.71b).................................................... 976 iv. ECL1 (K202-L218). ......................................................... 977 v. TM3 (S2193.22b-A2563.59b).................................................... 977 vi. ICL2 (F257-I265)............................................................ 978 vii. TM4 (F2664.42b-Y2914.62b).................................................... 978 viii. ECL2 (E292-Y305). ......................................................... 978 ix. TM5 (W3065.36b-K3365.66b)................................................... 978 x. ICL3 (A337-T343). .......................................................... 979 xi. TM6 (D3446.33b-F3696.58b)................................................... 979 xii. ECL3 (V370-G377). ......................................................... 979 xiii. TM7 (Y3787.33b-Y4027.57b).................................................... 979 xiv. C terminus (C404-S463). .................................................... 979 C. Receptor Function ...................................................................... 979 1. Signaling. ........................................................................... 980 a. Recombinant cells. ............................................................... 980 b. Pancreatic b cells................................................................. 980 i. Insulin Secretion. ........................................................... 980 ii. Insulin Synthesis and Storage. .............................................. 981 iii. b Cell Survival, Proliferation, and Neogenesis.. .............................. 981 c. Extrapancreatic signaling.. ..................................................... 982 i. Liver........................................................................ 982 ii. Kidney. ..................................................................... 982 iii. Adipocytes. ................................................................. 983 iv. Nervous System.. ........................................................... 983 v. Cardiovascular System. ..................................................... 983 2. Ligand-Directed Signal Bias. ..................................................... 983 a. Peptide-mediated signal bias. .................................................... 983 b. Nonpeptide-mediated bias. ..................................................... 984 ABBREVIATIONS: Ab, amyloid b protein; AD, Alzheimer’s disease; Aib, aminoisobutyric acid; AMPK, AMP-activated protein kinase; BCM, b cell mass; BETP, 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine; CD, circular dichroism; CHI, congenital hyperinsulinism; CHL, Chinese hamster lung; CHO, Chinese hamster ovary; CICR, calcium-induced calcium release; CNS, central nervous system; CREB, cAMP response element-binding protein; CRF1R, corticotropin-releasing