title: Functionally biased signalling properties of 7TM receptors - opportunities for drug development for the ghrelin receptor.
abstract: The ghrelin receptor is a 7 transmembrane (7TM) receptor involved in a variety of physiological functions including growth hormone secretion, increased food intake and fat accumulation as well as modulation of reward and cognitive functions. Because of its important role in metabolism and energy expenditure, the ghrelin receptor has become an important therapeutic target for drug design and the development of anti-obesity compounds. However, none of the compounds developed so far have been approved for commercial use. Interestingly, the ghrelin receptor is able to signal through several different signalling pathways including Gαq , Gαi/o , Gα12/13 and arrestin recruitment. These multiple signalling pathways allow for functionally biased signalling, where one signalling pathway may be favoured over another either by selective ligands or through mutations in the receptor. In the present review, we have described how ligands and mutations in the 7TM receptor may bias the receptors to favour either one G-protein over another or to promote G-protein independent signalling pathways rather than G-protein-dependent pathways. For the ghrelin receptor, both agonist and inverse agonists have been demonstrated to signal more strongly through the Gαq -coupled pathway than the Gα12/13 -coupled pathway. Similarly a ligand that promotes Gαq coupling over Gαi coupling has been described and it has been suggested that several different active conformations of the receptor may exist dependent on the properties of the agonist. Importantly, ligands with such biased signalling properties may allow the development of drugs that selectively modulate only the therapeutically relevant physiological functions, thereby decreasing the risk of side effects.
  
  
  BACKGROUND
  This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, the Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Sivertsen
authors.forename: N
authors.initials: N
authors.lastname: Holliday
authors.forename: A N
authors.initials: AN
authors.lastname: Madsen
authors.forename: B
authors.initials: B
authors.lastname: Holst
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000627:therapeutic use*; D001069:Appetite Regulation / Q000187:drug effects; D015195:Drug Design; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011487:Protein Conformation; D054440:Receptors, Ghrelin / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D008024:Ligands; D054440:Receptors, Ghrelin
keywords: 7TM receptor; GPCR; biased agonism; biased signalling; ghrelin receptor
references.citation: Sci Signal. 2011 Aug 9;4(185):ra51
references.pmid: 21868357
references.citation: J Biol Chem. 2004 Dec 17;279(51):53806-17
references.pmid: 15383539
references.citation: Mol Endocrinol. 2006 Aug;20(8):1772-85
references.pmid: 16601073
references.citation: J Pharmacol Exp Ther. 2004 Mar;308(3):880-6
references.pmid: 14634050
references.citation: Br J Pharmacol. 2012 Mar;165(6):1659-1669
references.pmid: 22023017
references.citation: J Med Chem. 2007 Nov 15;50(23):5790-806
references.pmid: 17927165
references.citation: J Biol Chem. 1998 Jul 17;273(29):17979-82
references.pmid: 9660746
references.citation: Mol Pharmacol. 2009 Oct;76(4):802-11
references.pmid: 19625579
references.citation: J Clin Endocrinol Metab. 2003 Sep;88(9):4268-72
references.pmid: 12970297
references.citation: J Biol Chem. 2012 Sep 28;287(40):33488-502
references.pmid: 22846991
references.citation: Neuroendocrinology. 2012;96(1):24-31
references.pmid: 22343549
references.citation: FEBS J. 2005 Jun;272(12):2947-55
references.pmid: 15955055
references.citation: J Clin Endocrinol Metab. 2004 Jun;89(6):3062-5
references.pmid: 15181099
references.citation: Mol Cell Endocrinol. 2011 Jun 20;340(1):80-7
references.pmid: 21354264
references.citation: Mol Pharmacol. 2009 Jan;75(1):44-59
references.pmid: 18923064
references.citation: Biochem Biophys Res Commun. 2002 Dec 20;299(5):739-43
references.pmid: 12470640
references.citation: Endocrinology. 2007 Nov;148(11):5175-85
references.pmid: 17656463
references.citation: J Clin Endocrinol Metab. 2000 Oct;85(10):3803-7
references.pmid: 11061542
references.citation: Endocr Rev. 2004 Jun;25(3):426-57
references.pmid: 15180951
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11086-91
references.pmid: 12960366
references.citation: Nature. 1999 Dec 9;402(6762):656-60
references.pmid: 10604470
references.citation: J Clin Invest. 2001 Oct;108(8):1167-74
references.pmid: 11602624
references.citation: Proc Natl Acad Sci U S A. 2012 May 22;109(21):8304-9
references.pmid: 22573814
references.citation: Nature. 2008 Aug 14;454(7206):846-51
references.pmid: 18668043
references.citation: Mol Pharmacol. 2006 Sep;70(3):936-46
references.pmid: 16798937
references.citation: Nat Chem Biol. 2011 Aug 21;7(10):692-700
references.pmid: 21857662
references.citation: PLoS One. 2011;6(11):e26865
references.pmid: 22102869
references.citation: Mol Pharmacol. 1998 Jul;54(1):94-104
references.pmid: 9658194
references.citation: J Cardiovasc Pharmacol. 2004 Feb;43(2):165-70
references.pmid: 14716201
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6733-8
references.pmid: 22493271
references.citation: J Clin Endocrinol Metab. 2002 Jun;87(6):2988
references.pmid: 12050285
references.citation: Br J Pharmacol. 2006 Jun;148(3):350-65
references.pmid: 16582936
references.citation: Science. 2012 Mar 2;335(6072):1106-10
references.pmid: 22267580
references.citation: Neuron. 2012 Jan 26;73(2):317-32
references.pmid: 22284186
references.citation: Br J Pharmacol. 2011 Nov;164 Suppl 1:S1-324
references.pmid: 22040146
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10782-7
references.pmid: 12949261
references.citation: Nature. 2007 Nov 15;450(7168):383-7
references.pmid: 17952055
references.citation: Eur J Pharmacol. 2010 Sep 25;643(2-3):153-61
references.pmid: 20599926
references.citation: Endocr Rev. 1997 Oct;18(5):621-45
references.pmid: 9331545
references.citation: Neuroendocrinology. 2012;95(4):277-88
references.pmid: 22327910
references.citation: Science. 1996 Aug 16;273(5277):974-7
references.pmid: 8688086
references.citation: J Mol Neurosci. 2011 Feb;43(2):193-9
references.pmid: 20596792
references.citation: Nature. 1996 Sep 26;383(6598):347-50
references.pmid: 8848049
references.citation: J Cardiovasc Pharmacol. 2012 May;59(5):465-71
references.pmid: 22269847
references.citation: J Biol Chem. 1995 Dec 15;270(50):30068-74
references.pmid: 8530411
references.citation: Nature. 2011 Jul 19;477(7366):549-55
references.pmid: 21772288
references.citation: Mol Endocrinol. 1998 Jan;12(1):137-45
references.pmid: 9440817
references.citation: J Biol Chem. 2006 Dec 15;281(50):38812-24
references.pmid: 17015451
references.citation: Nature. 2011 Sep 28;477(7366):540-1
references.pmid: 21956322
references.citation: Science. 2008 Nov 21;322(5905):1211-7
references.pmid: 18832607
references.citation: Trends Pharmacol Sci. 2007 Aug;28(8):416-22
references.pmid: 17644195
references.citation: J Biol Chem. 2010 Mar 5;285(10):7459-74
references.pmid: 20051519
references.citation: J Clin Endocrinol Metab. 1990 Apr;70(4):975-82
references.pmid: 2108187
references.citation: J Biol Chem. 2011 Jun 24;286(25):22622-31
references.pmid: 21525003
references.citation: Annu Rev Pharmacol Toxicol. 2008;48:537-68
references.pmid: 18184106
references.citation: J Pharmacol Exp Ther. 2005 Jun;313(3):1281-8
references.pmid: 15743921
references.citation: Trends Pharmacol Sci. 1995 Jun;16(6):188-92
references.pmid: 7652927
references.citation: Diabetes. 2001 Apr;50(4):707-9
references.pmid: 11289032
references.citation: Pharmacol Rev. 2010 Jun;62(2):265-304
references.pmid: 20392808
references.citation: Horm Res. 2003;59(3):109-17
references.pmid: 12637790
references.citation: Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):5061-5
references.pmid: 1647024
references.citation: J Biol Chem. 1996 Dec 27;271(52):33575-9
references.pmid: 8969224
references.citation: J Biol Chem. 2005 Jun 10;280(23):22165-71
references.pmid: 15817484
references.citation: J Biol Chem. 2002 Mar 15;277(11):9268-77
references.pmid: 11777928
references.citation: J Clin Invest. 2006 Dec;116(12):3229-39
references.pmid: 17060947
references.citation: J Biol Chem. 2013 Jan 4;288(1):181-91
references.pmid: 23161547
references.citation: J Biol Chem. 2010 Nov 12;285(46):36188-98
references.pmid: 20837485
references.citation: Cell Metab. 2008 May;7(5):389-99
references.pmid: 18460330
references.citation: Mol Pharmacol. 2010 Jan;77(1):1-9
references.pmid: 19837905
references.citation: Rev Endocr Metab Disord. 2011 Dec;12(4):259-74
references.pmid: 21526415
references.citation: J Biol Chem. 2011 Jun 10;286(23):20845-60
references.pmid: 21402696
references.citation: Expert Opin Drug Discov. 2010 Nov;5(11):1109-22
references.pmid: 21132095
references.citation: Science. 1991 Dec 6;254(5037):1500-3
references.pmid: 1962211
references.citation: Diabetes. 2001 Aug;50(8):1714-9
references.pmid: 11473029
references.citation: J Biol Chem. 2013 May 3;288(18):12511-21
references.pmid: 23493400
references.citation: Mol Cell Endocrinol. 2011 Jan 15;331(2):232-40
references.pmid: 20674667
references.citation: Nat Rev Drug Discov. 2011 Aug 01;10(8):579-90
references.pmid: 21804595
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11381-6
references.pmid: 12172010
references.citation: Trends Pharmacol Sci. 1995 Jul;16(7):232-8
references.pmid: 7667897
references.citation: Br J Pharmacol. 2008 Mar;153 Suppl 1:S216-29
references.pmid: 17965750
references.citation: Science. 1996 Nov 1;274(5288):768-70
references.pmid: 8864113
references.citation: J Biol Chem. 2009 Sep 25;284(39):26411-20
references.pmid: 19648111
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18607-12
references.pmid: 23091034
references.citation: Diabetes. 2011 Apr;60(4):1177-85
references.pmid: 21386086
references.citation: J Pharmacol Exp Ther. 1998 Aug;286(2):593-8
references.pmid: 9694908
references.citation: J Med Chem. 2007 Oct 18;50(21):5202-16
references.pmid: 17887659
references.citation: J Biol Chem. 2012 Feb 3;287(6):3630-41
references.pmid: 22117076
references.citation: Mol Endocrinol. 2007 Dec;21(12):3100-12
references.pmid: 17717076
references.citation: Nature. 2010 Jan 7;463(7277):108-12
references.pmid: 20054398
references.citation: JAMA. 1994 Mar 2;271(9):672-7
references.pmid: 8309029
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11318-23
references.pmid: 19564604
references.citation: J Biol Chem. 2005 Dec 16;280(50):41769-76
references.pmid: 16221676
references.citation: PLoS One. 2012;7(11):e49557
references.pmid: 23166710
references.citation: Nature. 1994 Jun 2;369(6479):418-20
references.pmid: 8196770
references.citation: FASEB J. 2010 Aug;24(8):2670-9
references.pmid: 20335227
references.citation: Mol Endocrinol. 2005 Sep;19(9):2400-11
references.pmid: 15905359
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):549-77
references.pmid: 18253722
references.citation: J Med Chem. 2006 Jul 27;49(15):4459-69
references.pmid: 16854051
references.citation: Circulation. 2001 Oct 23;104(17):2034-8
references.pmid: 11673342
references.citation: J Clin Endocrinol Metab. 2001 Apr;86(4):1464-9
references.pmid: 11297568
references.citation: J Pharmacol Exp Ther. 2007 Jun;321(3):1193-207
references.pmid: 17392404
references.citation: EMBO J. 1999 Jul 15;18(14):4004-12
references.pmid: 10406805
references.citation: Mol Endocrinol. 2003 Nov;17(11):2201-10
references.pmid: 12907757
references.citation: Nature. 2011 May 18;474(7352):521-5
references.pmid: 21593763
references.citation: J Biol Chem. 2007 Jun 22;282(25):18028-18036
references.pmid: 17452318
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7157-62
references.pmid: 9618555
references.citation: Int J Biochem Cell Biol. 2007;39(4):752-64
references.pmid: 17169600
references.citation: Nature. 2000 Oct 19;407(6806):908-13
references.pmid: 11057670
references.citation: Curr Diabetes Rev. 2011 May;7(3):201-7
references.pmid: 21539509
references.citation: Neuroendocrinology. 2011;94(2):158-68
references.pmid: 21778696
references.citation: Endocrinology. 2003 Jun;144(6):2220-8
references.pmid: 12746278
references.citation: Circ Heart Fail. 2011 Nov;4(6):770-8
references.pmid: 21835984
references.citation: Psychopharmacology (Berl). 2009 Oct;206(3):415-27
references.pmid: 19652956
references.citation: Eur J Endocrinol. 2004 Aug;151 Suppl 1:S71-5
references.pmid: 15339248
references.citation: Biochem Biophys Res Commun. 2007 Feb 9;353(2):238-43
references.pmid: 17184731
references.citation: Expert Opin Drug Discov. 2011 Aug;6(8):811-25
references.pmid: 22651124
references.citation: PLoS One. 2012;7(10):e46923
references.pmid: 23056530
references.citation: ChemMedChem. 2010 Sep 3;5(9):1450-5
references.pmid: 20593439
references.citation: J Biol Chem. 2007 May 25;282(21):15799-811
references.pmid: 17371869
references.citation: J Pharmacol Exp Ther. 2010 Dec;335(3):572-9
references.pmid: 20801892
references.citation: Eur J Biochem. 1988 Aug 1;175(2):331-8
references.pmid: 2900138
references.citation: Nat Neurosci. 2006 Mar;9(3):381-8
references.pmid: 16491079
references.citation: Nature. 2010 Apr 29;464(7293):1386-9
references.pmid: 20383122
references.citation: Cell Metab. 2007 Jun;5(6):450-63
references.pmid: 17550780
references.citation: J Am Geriatr Soc. 2004 Apr;52(4):516-23
references.pmid: 15066065
references.citation: J Biol Chem. 1993 Dec 5;268(34):25952-7
references.pmid: 8245028
references.citation: Trends Pharmacol Sci. 2009 Sep;30(9):460-9
references.pmid: 19729207
references.citation: Brain Res Mol Brain Res. 1997 Aug;48(1):23-9
references.pmid: 9379845
references.citation: J Clin Endocrinol Metab. 2001 Mar;86(3):1116-25
references.pmid: 11238495