Minireview: Signal bias, allosterism, and polymorphic variation at the GLP-1R: Implications for drug discovery

Molecular Endocrinology

Volumn 27, Issue 8, 2013, Pages 1234-1244

  Koole, Cassandra ^a   Savage, Emilia E ^a   Christopoulos, Arthur ^a   Miller, Laurence J ^b   Sexton, Patrick M ^a   Wootten, Denise ^a  

^a MONASH UNIVERSITY   (Australia)

^b MAYO GRADUATE SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,3 BIS [[4 (TERT BUTOXYCARBONYLAMINO)BENZOYL]AMINO] 2,4 BIS[3 METHOXY 4 (THIOPHENE 2 CARBONYLOXY)PHENYL]CYCLOBUTANE 1,3 DICARBOXYLIC ACID; 4 (3 BENZYLOXYPHENYL) 2 ETHYLSULFINYL 6 (TRIFLUOROMETHYL)PYRIMIDINE; BETA ARRESTIN 1; BRISTOL MYERS SQUIBB COMPANY PEPTIDE 21; CALCIUM ION; CARBOXYLIC ACID DERIVATIVE; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; EXENDIN 4; FLAVONOL DERIVATIVE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 [1-36] AMIDE; GLUCAGON LIKE PEPTIDE 1 [1-37]; GLUCAGON LIKE PEPTIDE 1 [7-36] AMIDE; GLUCAGON LIKE PEPTIDE 1 [7-37]; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; LIRAGLUTIDE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; OXYNTOMODULIN; PEPTIDE; PHOSPHATIDYLINOSITOL 3 KINASE; POTASSIUM CHANNEL; PROGLUCAGON; PROPIONIC ACID DERIVATIVE; PYRIMIDINE DERIVATIVE; TT 15; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALLOSTERISM; CALCIUM MOBILIZATION; CELL MEMBRANE DEPOLARIZATION; DIABETIC OBESITY; DIMERIZATION; DRUG MECHANISM; GENE MUTATION; GENETIC VARIABILITY; GLUCOSE HOMEOSTASIS; HETEROZYGOTE; HOMOZYGOTE; HORMONE ACTION; HORMONE METABOLISM; HUMAN; INSULIN RELEASE; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS CANCER; PANCREAS ISLET BETA CELL; PANCREATITIS; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; RECEPTOR DOWN REGULATION; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; WEIGHT REDUCTION;

ALLOSTERIC REGULATION; AMINO ACID SEQUENCE; DIABETES MELLITUS, TYPE 2; DRUG DISCOVERY; GLUCAGON-LIKE PEPTIDE 1; GLUCOSE; HUMANS; INCRETINS; INSULIN; MOLECULAR SEQUENCE DATA; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTORS, GLUCAGON; SIGNAL TRANSDUCTION;

EID: 84880810520     PISSN: 08888809     EISSN: None     Source Type: Journal    
DOI: 10.1210/me.2013-1116     Document Type: Review

References (89)

1. Reimann F. Molecular mechanisms underlying nutrient detection by incretin-secreting cells. Int Dairy J. 2010;20:236-242.
2. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
3. Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion. 1995; 56:117-126.
4. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon- like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A. 1987;84:3434-3438.
5. Orskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology. 1988;123:2009-2013.
6. Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ. Glucagon- like peptide-1 receptor signaling modulates β cell apoptosis. J Biol Chem. 2003;278:471-478.
7. Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003;144:5149-5158.
8. Ling Z, Wu D, Zambre Y, et al. Glucagon-like peptide 1 receptor signaling influences topography of islet cells in mice. Virchows Arch. 2001;438:382-387.
9. Dunphy JL, Taylor RG, Fuller PJ. Tissue distribution of rat glucagon receptor and GLP-1 receptor gene expression. Mol Cell Endocrinol. 1998;141:179-186.
10. Larsen PJ, Tang-Christensen M, Jessop DS. Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology. 1997;138:4445-4455.
11. During MJ, Cao L, Zuzga DS, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003;9: 1173-1179.
12. Nystrom T. The potential beneficial role of glucagon-like peptide-1 in endothelial dysfunction and heart failure associated with insulin resistance. Horm Metab Res. 2008;40:593-606.
13. Bose AK, Mocanu MM, Carr RD, Yellon DM. Myocardial ischaemia- reperfusion injury is attenuated by intact glucagon like peptide- 1 (GLP-1) in the in vitro rat heart and may involve the p70s6K pathway. Cardiovasc Drugs Ther. 2007;21:253-256.
14. Gros R, You X, Baggio LL, et al. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003;144: 2242-2252.
15. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993;38:665-673.
16. Young AA, Gedulin BR, Bhavsar S, et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes. 1999;48:1026-1034.
17. Prigeon RL, Quddusi S, Paty B, D'Alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab. 2003;285: E701-E707.
18. Richter G, Feddersen O, Wagner U, Barth P, Goke R, Goke B. GLP-1 stimulates secretion of macromolecules from airways and relaxes pulmonary artery. Am J Physiol. 1993;265:L374-L381.
19. Gutzwiller JP, Hruz P, Huber AR, et al. Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans. Digestion. 2006;73:142-150.
20. Montrose-Rafizadeh C, Avdonin P, Garant MJ, et al. Pancreatic glucagon-like peptide-1 receptor couples to multipleGproteins and activates mitogen-activated protein kinase pathways in Chinese hamster ovary cells. Endocrinology. 1999;140:1132-1140.
21. Sonoda N, Imamura T, Yoshizaki T, Babendure JL, Lu JC, Olefsky JM. β-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic β cells. Proc Natl Acad Sci USA. 2008;105:6614-6619.
22. Quoyer J, Longuet C, Broca C, et al. GLP-1 mediates antiapoptotic effect by phosphorylating Bad through a β-arrestin 1-mediated ERK1/2 activation in pancreatic β-cells. J Biol Chem. 2010;285: 1989-2002.
23. Holz GG. Epac: anew cAMP-binding protein in support of glucagon- like peptide-1 receptor-mediated signal transduction in the pancreatic β-cell. Diabetes. 2004;53:5-13.
24. MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes. 2002;51:S434-S442.
25. Drucker DJ, Jin T, Asa SL, Young TA, Brubaker PL. Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line. Mol Endocrinol. 1994;8:1646-1655.
26. Drucker DJ, Brubaker PL. Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. Proc Natl Acad Sci USA. 1989;86:3953-3957.
27. Arnette D, Gibson TB, Lawrence MC, et al. Regulation of ERK1 and ERK2 by glucose and peptide hormones in pancreatic β cells. J Biol Chem. 2003;278:32517-32525.
28. Buteau J, Foisy S, Rhodes CJ, Carpenter L, Biden TJ, Prentki M. Protein kinase Cβ activation mediates glucagon-like peptide-1-induced pancreatic β-cell proliferation. Diabetes. 2001;50:2237-2243.
29. Park S, Dong X, Fisher TL, et al. Exendin-4 uses Irs2 signaling to mediate pancreatic β cell growth and function. J Biol Chem. 2006; 281:1159-1168.
30. Khoo S, Griffen SC, Xia Y, Baer RJ, German MS, Cobb MH. Regulation of insulin gene transcription by ERK1 and ERK2 in pancreatic β cells. J Biol Chem. 2003;278:32969-32977.
31. Buteau J, Foisy S, Joly E, Prentki M. Glucagon-like peptide 1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes. 2003;52:124-132.
32. Farilla L, Hui H, Bertolotto C, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology. 2002;143:4397-4408.
33. Holz GG, Kuhtreiber WM, Habener JF. Pancreatic β-cells are rendered glucose-competent by the insulinotropic hormone glucagonlike peptide-1(7-37). Nature. 1993;361:362-365.
34. Syme CA, Zhang L, Bisello A. Caveolin-1 regulates cellular trafficking and function of the glucagon-like peptide 1 receptor. Mol Endocrinol. 2006;20:3400-3411.
35. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide- 1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-1705.
36. Nauck M, Frid A, Hermansen K, Shah NS, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32:84-90.
37. Robles GI, Singh-Franco D. A review of exenatide as adjunctive therapy in patients with type 2 diabetes. Drug Des Dev Ther. 2009; 3:219-240.
38. Cure P, Pileggi A, Alejandro R. Exenatide and rare adverse events. N Engl J Med. 2008;358:1969-1970; discussion 1971-1962.
39. Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a populationbased matched case-control study. JAMA Intern Med. 2013;173: 534-539.
40. Knudsen LB, Kiel D, Teng M, et al. Small-molecule agonists for the glucagon-like peptide 1 receptor. Proc Natl Acad Sci USA. 2007; 104:937-942.
41. Sloop KW, Willard FS, Brenner MB, et al. Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets. Diabetes. 2010;59:3099-3107.
42. Chen D, Liao J, Li N, et al. A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. Proc Natl Acad Sci USA. 2007;104:943-948.
43. Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov. 2006;5:993-996.
44. Kenakin T. Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther. 2011;336:296-302.
45. Koole C, Wootten D, Simms J, et al. Allosteric ligands of the glucagon- like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: Implications for drug screening. Mol Pharmacol. 2010;78: 456-465.
46. Willard FS, Wootten D, Showalter AD, et al. Small molecule allosteric modulation of the glucagon-like peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin. Mol Pharmacol. 2012; 82:1066-1073.
47. Wootten D, Savage EE, Willard FS, et al. Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands. Mol Pharmacol. 2013;83:822-834.
48. Kenakin T, Watson C, Muniz-Medina V, Christopoulos A, Novick S. A simple method for quantifying functional selectivity and agonist bias. ACS Chem Neurosci. 2012;3:193-203.
49. Black JW, Leff P. Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci. 1983;220:141-162.
50. Wootten D, Simms J, Miller LJ, Christopoulos A, Sexton PM. Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations. Proc Natl Acad Sci USA. 2013;110:5211-5216.
51. Schelshorn D, Joly F, Mutel S, et al. Lateral allosterism in the glucagon receptor family: glucagon-like peptide 1 induces G-proteincoupled receptor heteromer formation. Mol Pharmacol. 2012;81: 309-318.
52. Wootten D, Savage EE, Valant C, May LT, et al. Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol. 2012;82:281-290.
53. Mapelli C, Natarajan SI, Meyer JP, et al. Eleven amino acid gluca gon-like peptide-1 receptor agonists with antidiabetic activity. J Med Chem. 2009;52:7788-7799.
54. Coopman K, Huang Y, Johnston N, Bradley SJ, Wilkinson GF, Willars GB. Comparative effects of the endogenous agonist glucagon- like peptide-1 (GLP-1)-(7-36) amide and the small-molecule ago-allosteric agent "compound 2" at the GLP-1 receptor. J Pharmacol Exp Ther. 2010;334:795-808.
55. Monod J, Changeux JP, Jacob F. Allosteric proteins and cellular control systems. J Mol Biol. 1963;6:306-329.
56. Monod J, Wyman J, Changeux JP. On the nature of allosteric transitions: a plausible model. J Mol Biol. 1965;12:88-118.
57. Canals M, Sexton PM, Christopoulos A. Allostery in GPCRs: 'MWC' revisited. Trends Biochem Sci. 2011;36(12):663-672.
58. Keov P, Sexton PM, Christopoulos A. Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology. 2011;60:24-35.
59. Wootten D, Simms J, Koole C, et al. Modulation of the glucagonlike peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther. 2011;336:540-550.
60. Price MR, Baillie GL, Thomas A, et al. Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol. 2005;68:1484-1495.
61. Maillet EL, Pellegrini N, Valant C, et al. A novel, conformationspecific allosteric inhibitor of the tachykinin NK2 receptor (NK2R) with functionally selective properties. FASEB J. 2007;21:2124-2134.
62. Irwin N, Flatt PR, Patterson S, Green BD. Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7- dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline. Eur J Pharmacol. 2010;628:268-273.
63. DeFronzo RA. Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia. 1992;35:389-397.
64. Li N, Lu J, Willars GB. Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1) metabolite GLP-1 9-36 amide at the GLP-1 receptor. PLoS ONE. 2012;7:e47936.
65. Rondard P, Goudet C, Kniazeff J, Pin JP, Prezeau L. The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein-coupled receptors. Neuropharmacology. 2011;60:82-92.
66. Ding WQ, Cheng ZJ, McElhiney J, Kuntz SM, Miller LJ. Silencing of secretin receptor function by dimerization with a misspliced variant secretin receptor in ductal pancreatic adenocarcinoma. Cancer Res. 2002;62:5223-5229.
67. Whitaker GM, Lynn FC, McIntosh CH, Accili EA. Regulation of GIP and GLP1 receptor cell surface expression by N-glycosylation and receptor heteromerization. PLoS ONE. 2012;7:e32675.
68. Harikumar KG, Morfis MM, Lisenbee CS, Sexton PM, Miller LJ. Constitutive formation of oligomeric complexes between family B G protein-coupled vasoactive intestinal polypeptide and secretin receptors. Mol Pharmacol. 2006;69:363-373.
69. Harikumar KG, Wootten D, Pinon DI, et al. Glucagon-like peptide- 1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery. Proc Natl Acad Sci USA. 2012;109:18607-18612.
70. Harikumar KG, Ball AM, Sexton PM, Miller LJ. Importance of lipid-exposed residues in transmembrane segment four for family B calcitonin receptor homo-dimerization. Regul Pept. 2010;164: 113-119.
71. Harikumar KG, Pinon DI, Miller LJ. Transmembrane segment IV contributes a functionally important interface for oligomerization of the class II G protein-coupled secretin receptor. J Biol Chem. 2007;282:30363-30372.
72. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2β)-sensing receptor from bovine parathyroid. Nature. 1993;366:575-580.
73. Brown EM. The calcium-sensing receptor (CaR) and its disorders. Hormones (Athens). 2002;1:10-21.
74. Brown EM. The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell Biochem. 2007;45: 139-167.
75. Schipani E, Kruse K, Juppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science. 1995;268:98-100.
76. Schipani E, Langman CB, et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med. 1996; 335:708-714.
77. Schipani E, Jensen GS, Pincus J, Nissenson RA, Gardella TJ, Juppner H. Constitutive activation of the cyclic adenosine 3β,5β-monophosphate signaling pathway by parathyroid hormone (PTH)/ PTH-related peptide receptors mutated at the two loci for Jansen's metaphyseal chondrodysplasia. Mol Endocrinol. 1997;11:851-858.
78. Hager J, Hansen L, Vaisse C, et al. A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus. Nat Genet. 1995;9:299-304.
79. Siani A, Iacone R, Russo O, et al. Gly40Ser polymorphism of the glucagon receptor gene is associated with central adiposity in men. Obes Res. 2001;9:722-726.
80. Beinborn M, Worrall CI, McBride EW, Kopin AS. A human glucagon- like peptide-1 receptor polymorphism results in reduced agonist responsiveness. Regul Pept. 2005;130:1-6.
81. Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A. Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract. 2004;66:63-69.
82. Fortin JP, Schroeder JC, Zhu Y, Beinborn M, Kopin AS. Pharmacological characterization of human incretin receptor missense variants. J Pharmacol Exp Ther. 2010;332:274-280.
83. Koole C, Wootten D, Simms J, et al. Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation. Mol Pharmacol. 2011;80:486-497.
84. Koole C, Wootten D, Simms J, et al. Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) differentially regulates orthosteric but not allosteric agonist binding and function. J Biol Chem. 2012;287:3659-3673.
85. Hoare SR. Mechanisms of peptide and nonpeptide ligand binding to class B G-protein-coupled receptors. Drug Discov Today. 2005; 10:417-427.
86. Newton CL, Whay AM, McArdle CA, et al. Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist. Proc Natl Acad Sci USA. 2011;108:7172-7176.
87. White E, McKenna J, Cavanaugh A, Breitwieser GE. Pharmacochaperone- mediated rescue of calcium-sensing receptor loss-offunction mutants. Mol Endocrinol. 2009;23:1115-1123.
88. Huang Y, Breitwieser GE. Rescue of calcium-sensing receptor mutants by allosteric modulators reveals a conformational checkpoint in receptor biogenesis. J Biol Chem. 2007;282:9517-9525.
89. Kenakin T, Christopoulos A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov. 2012;12:205-216.