Signaling mechanisms of GPCR ligands

Current Opinion in Drug Discovery and Development

Volumn 11, Issue 2, 2008, Pages 196-202

  Strange, Philip G ^a  

^a UNIVERSITY OF READING   (United Kingdom)

Author keywords

Conformational change; Efficacy; G protein coupled receptors; Heterodimer; Signaling mechanisms; Structure and organization

Indexed keywords

3 AMINO 3 METHYL N [2,3,4,5 TETRAHYDRO 2 OXO 1 [[2' (1H TETRAZOL 5 YL) 1,1' BIPHENYL 4 YL]METHYL] 1H 1 BENZAZEPIN 3 YL]BUTANAMIDE; 4 (3 TERT BUTYLAMINO 2 HYDROXYPROPOXY) 2 BENZIMIDAZOLONE; ADENYLATE CYCLASE; ADRENALIN; ALPHA 2A ADRENERGIC RECEPTOR; BETA 1 ADRENERGIC RECEPTOR; BETA 2 ADRENERGIC RECEPTOR; BRADYKININ B2 RECEPTOR; CARVEDILOL; CYAN FLUORESCENT PROTEIN; DOPAMINE 1 RECEPTOR; G PROTEIN COUPLED RECEPTOR; GHRELIN; GLYCOGEN SYNTHASE KINASE 3; GUANINE NUCLEOTIDE BINDING PROTEIN; GUANINE NUCLEOTIDE BINDING PROTEIN ALPHA SUBUNIT; GUANINE NUCLEOTIDE BINDING PROTEIN BETA SUBUNIT; HETERODIMER; ISOPRENALINE; LIGAND; LY 362884; MITOGEN ACTIVATED PROTEIN KINASE; PARTIAL AGONIST; PROPRANOLOL; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; PROTEINASE ACTIVATED RECEPTOR 1; RETINA S ANTIGEN; UNCLASSIFIED DRUG; UNINDEXED DRUG; YELLOW FLUORESCENT PROTEIN;

BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; DRUG BINDING SITE; DRUG DESIGN; FLUORESCENCE RESONANCE ENERGY TRANSFER; HUMAN; LIGAND BINDING; RECEPTOR UPREGULATION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; GTP-BINDING PROTEINS; HUMANS; LIGANDS; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 39549120033     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (53)

1. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M et al: Crystal structure of rhodopsin: A G protein-coupled receptor. Science (2000) 289(5480):739-745.
2. 2-adrenergic G protein-coupled receptor. Nature (2007) 450(7168):383-387. •• Reports the first structure of a GPCR for a diffusible ligand and drug target.
3. 2-adrenergic G protein-coupled receptor. Science (2007) 318(5854):1258-1265. •• Reports the first structure of a GPCR for a diffusible ligand and drug target.
4. 2-adrenergic receptor function. Science (2007) 318(5854):1266-1273. •• Reports the first structure of a GPCR for a diffusible ligand and drug target.
5. Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A: Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem (2003) 278(24):21655-21662.
6. Milligan G: A day in the life of a G protein-coupled receptor: The contribution to function of G protein-coupled receptor dimerization. Br J Pharmacol (2007): epublished ahead of print. DOI:10.1038/sj.bjp.0707490.
7. 2 muscarinic cholinergic receptor are reconstituted into phospholipid vesicles. Biochemistry (2007) 46(26):7907-7927. • Provides a recent study supporting the idea that GPCRs are oligomeric.
8. 2 dopamine receptor. Mol Pharmacol (2006) 69(1):226-235.
9. 3H]raclopride to rat and human brain membranes. J Neurochem (1990) 55(6):2048-2057.
10. White JF, Grodnitzky J, Louis JM, Trinh LB, Shiloach J, Gutierrez J, Northup JK, Grisshammer R: Dimerization of the class A G protein-coupled neurotensin receptor NTS1 alters G protein interaction. Proc Natl Acad Sci USA (2007) 104(29):12199-12204.
11. Whorton MR, Bokoch MP, Rasmussen SG, Huang B, Zare RN, Kobilka B, Sunahara RK: A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc Natl Acad Sci USA (2007) 104(18):7682-7687.
12. Kniazeff J, Bessis AS, Maurel D, Ansanay H, Prézeau L, Pin JP: Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat Struct Mol Biol (2004) 11(8):706-713.
13. Damian M, Martin A, Mesnier D, Pin JP, Banères JL: Asymmetric conformational changes in a GPCR dimer controlled by G-proteins. EMBO J (2006) 25(24):5693-5702.
14. James JR, Oliveira MI, Carmo AM, Iaboni A, Davis SJ: A rigorous experimental framework for detecting protein oligomerization using bioluminescence resonance energy transfer. Nat Methods (2006) 3(12):1001-1006. • Questions the technological basis for some of the research on GPCR dimers; such challenges are important so that methods are properly scrutinized. See also the discussions in references [15] and [16].
15. Bouvier M, Heveker N, Jockers R, Marullo S, Milligan G: BRET analysis of GPCR oligomerization: Newer does not mean better. Nat Methods (2007) 4(1):3-4; author reply 4.
16. Salahpour A, Masri B: Experimental challenge to a 'rigorous' BRET analysis of GPCR oligomerization. Nat Methods (2007) 4(8):599-600; author reply 601.
17. Kobilka BK: G protein-coupled receptor structure and activation. Biochim Biophys Acta (2007) 1768(4):794-807. • Summarizes much of the careful biophysical and biochemical research on GPCR mechanisms.
18. 2-Adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J Biol Chem (2002) 277(43):40989-40996.
19. Ballesteros JA, Weinstein H: Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci (1995) 25:366-428.
20. Schwartz TW, Frimurer TM, Holst B, Rosenkilde MM, Elling CE: Molecular mechanism of 7TM receptor activation - A global toggle switch model. Annu Rev Pharmacol Toxicol (2006) 46:481-519.
21. 2-adrenoceptor. Nat Chem Biol (2006) 2(8):417-422.
22. 2-adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists. J Biol Chem (2005) 280(23):22165-22171.
23. Vilardaga JP, Bünemann M, Krasel C, Castro M, Lohse MJ: Measurement of the millisecond activation switch of G protein-coupled receptors in living cells. Nat Biotechnol (2003) 21(7):807- 812. •• Provides the first report of the use of a FRET sensor GPCR.
24. i protein heterotrimer. J Biol Chem (2006) 281(34):24506-24511.
25. Gilman AG: G proteins: Transducers of receptor-generated signals. Annu Rev Biochem (1987) 56:615-649.
26. Philip F, Sengupta P, Scarlata S: Signaling through a G protein-coupled receptor and its corresponding G protein follows a stoichiometrically limited model. J Biol Chem (2007) 282(26):19203-19216.
27. Hein P, Frank M, Hoffmann C, Lohse MJ, Bunemann M: Dynamics of receptor/G protein coupling in living cells. EMBO J (2005) 24(23):4106-4114.
28. i1 protein complex measured by bioluminescence resonance energy transfer in living cells. Mol Pharmacol (2007) 71(5):1329-1340.
29. Nobles M, Benians A, Tinker A: Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells. Proc Natl Acad Sci USA (2005) 102(51):18706-18711.
30. Durm JJ, Schaak S, Pontier S, Percherancier Y, Audet M, Paris H, Bouvier M: Probing the activation-promoted structural rearrangements in preassembled receptor-G protein complexes. Nat Struct Mol Biol (2006) 13(9):778-786.
31. 2 dopamine receptor: Evidence for persistent receptor/G protein interaction after agonist stimulation. Br J Pharmacol (2007) 151(1):144-152.
32. 2-adrenergic receptors. Proc Natl Acad Sci USA (2006) 103(1):212-217.
33. i protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci USA (2003) 100(26):16077-16082.
34. i- specific region. J Biol Chem (2005) 280(26):24584-24590.
35. s activation is time-limiting in initiating receptor-mediated signaling. J Biol Chem (2006) 281(44):33345-33351.
36. Ahn S, Shenoy SK, Wei H, Lefkowitz RJ: Differential kinetic and spatial patterns of β-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J Biol Chem (2004) 279(34):35518- 35525. • Describes different downstream signaling mechanisms for GPCRs.
37. 2-adrenergic receptor. J Biol Chem (2006) 281(2):1261-1273.
38. Sun Y, Huang J, Xiang Y, Bastepe M, Juppner H, Kobilka BK, Zhang JJ, Huang XY: Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR. EMBO J (2007) 26(1):53-64.
39. Beaulieu JM, Gainetdinov RR, Caron MG: The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci (2007) 28(4):166-172. • Reviews research that has uncovered an unexpected signaling pathway for GPCRs and shows its involvement in animal behavior.
40. Kenakin T: Efficacy as a vector: The relative prevalence and paucity of inverse agonism. Mol Pharmacol (2004) 65(1):2-11.
41. Strange PG: Mechanisms of inverse agonism at G protein-coupled receptors. Trends Pharmacol Sci (2002) 23(2):89-95.
42. 2-adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol Pharmacol (2006) 70(5):1575-1584. • Provides, together with reference [43], a novel insight into pathway-selective effects of drugs.
43. 2-adrenoceptor provide evidence for agonist-directed signaling. Mol Pharmacol (2003) 64(6):1357-1369. • Provides, together with reference [42], a novel insight into pathway-selective effects of drugs.
44. Holst B, Brandt E, Bach A, Heding A, Schwartz TW: Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. Mol Endocrinol (2005) 19(9):2400-2411.
45. 2 receptor dimer formation: Evidence from ligand binding. J Biol Chem (2001) 276(25):22621-22629.
46. 2. Mol Pharmacol (2005) 68(2):393-402.
47. Zhang Y, Rodriguez AL, Conn PJ: Allosteric potentiators of metabotropic glutamate receptor subtype 5 have differential effects on different signaling pathways in cortical astrocytes. J Pharmacol Exp Ther (2005) 315(3):1212-1219.
48. Baker JG, Hill SJ: Multiple GPCR conformations and signaling pathways: Implications for antagonist affinity estimates. Trends Pharmacol Sci (2007) 28(8):374-381.
49. Milligan G, Smith NJ: Allosteric modulation of heterodimeric G protein-coupled receptors. Trends Pharmacol Sci (2007) 28(12):615-620.
50. q/11-coupled dopamine receptors: An uncharted role for dopamine. Trends Pharmacol Sci (2007) 28(11):551-555. • Describes the role of a heterodimer in novel signaling responses.
51. Sohy D, Parmentier M, Springael JY: Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers. J Biol Chem (2007) 282(41):30062-30069.
52. Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, Portoghese PS, Whistler JL: A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci USA (2005) 102(25):9050-9055. • Describes the first compound selective for a GPCR heterodimer.
53. Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E, Diehl RE, Mumford RA et al: Cloning of the gene and cDNA for mammalian β-adrenergic receptor and homology with rhodopsin. Nature (1986) 321(6065):75-79.