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Structural Basis of Dopamine Receptor Activation

  • Irina S. Moreira
  • Lei Shi
  • Zachary Freyberg
  • Spencer S. Ericksen
  • Harel Weinstein
  • Jonathan A. Javitch
Chapter
Part of the The Receptors book series (REC)

Abstract

G protein-coupled receptors (GPCRs) are seven transmembrane (TM) proteins representing the largest and most universally expressed cell surface receptors and are present in almost all species and in a wide variety of cells. Here we will focus our attention on the catecholamine-binding GPCRs and in particular on the dopamine receptors. The catecholamine-binding GPCRs form a group of rhodopsin-like GPCRs composed of adrenoceptors, which are endogenously activated by epinephrine and norepinephrine, and dopamine receptors. We review the different “molecular switches” involved in GPCR activation and we emphasize the importance of extracellular loop 2 (ECL2) in ligand binding. A better understanding of the functional role of ECL2 can be achieved after the release of the crystal structures of B2AR and rhodopsin, which are consistent with dopamine D2 receptor substituted cysteine accessibility method (SCAM) experimental data. Even though reconstituted GPCR monomers appear sufficient to activate a G protein, in the native setting their dimerization/oligomerization may modulate activation through changes at the dimerization interface or a larger-scale reorientation of the protomers. Therefore, the structural aspects of oligomerization and their importance for receptor activation and signaling are also addressed.

Keywords

Catecholamine-binding GPCRs Dopamine receptors Binding site ECL2 GPCR oligomerization GPCR–G Protein interaction Activation Structural rearrangements 

References

  1. 1.
    Soyer O, Dimmic MW, Neubig RR, Goldstein RA. Using evolutionary methods to study G-protein coupled receptors. Pac Symp Biocomput 2002;7:625–36.Google Scholar
  2. 2.
    Soyer OS, Dimmic MW, Neubig RR, Goldstein RA. Dimerization in aminergic G-protein-coupled receptors: application of a hidden-site class model of evolution. Biochemistry 2003;42:14522–31.PubMedCrossRefGoogle Scholar
  3. 3.
    Bockaert J, Pin JP. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 1999;18:1723–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Avlani VA, Gregory KJ, Morton CJ, Parker MW, Sexton PM, Christopoulos A. Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands. J Biol Chem 2007.Google Scholar
  5. 5.
    Weinstein H. Protein interactions in GPCR signaling: a very moving story. Abstr Pap Am Chem Soc 2006;231:102.Google Scholar
  6. 6.
    Niv MY, Skrabanek L, Filizola M, Weinstein H. Modeling activated states of GPCRs: the rhodopsin template. J Comput Aided Mol Des 2006;20:437–48.PubMedCrossRefGoogle Scholar
  7. 7.
    Ballesteros J, Weinstein H. Integrated methods for the construction of three-dimensional models of structure-function relations in G protein-coupled receptors. Methods Neurosci 1995;25:366.CrossRefGoogle Scholar
  8. 8.
    Ballesteros JA, Shi L, Javitch JA. Structural mimicry in G-protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. Mol Pharmacol 2001;60:1.Google Scholar
  9. 9.
    Thompson, Menard, Pombal, Grillner. Forebrain dopamine depletion impairs motor behavior in lamprey. Eur J Neurosci 2008;27:1452–60.PubMedCrossRefGoogle Scholar
  10. 10.
    Chan WY, McKinzie DL, Bose S, et al. Allosteric modulation of the muscarinic M-4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A 2008;105:10978–83.PubMedCrossRefGoogle Scholar
  11. 11.
    Thompson MD, Burnham WM, Cole DE. The G protein-coupled receptors: pharmacogenetics and disease. Crit Rev Clin Lab Sci 2005;42:311–92.PubMedCrossRefGoogle Scholar
  12. 12.
    Palczewski K, Hofmann KP, Baehr W. Rhodopsin – advances and perspectives. Vision Res 2006;46:4425–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Bouchard C, Ribeiro P, Dube F, Anctil M. A new G protein-coupled receptor from a primitive metazoan shows homology with vertebrate aminergic receptors and displays constitutive activity in mammalian cells. J Neurochem 2003;86:1149–61.PubMedCrossRefGoogle Scholar
  14. 14.
    Klco JM, Wiegand CB, Narzinski K, Baranski TJ. Essential role for the second extracellular loop in C5a receptor activation. Nat Struct Mol Biol 2005;12:320–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Minneman K. Heterodimerization and surface localization of G protein coupled receptors. Special Issue: In Memory of Art Hancock 2007;73:1043–50.Google Scholar
  16. 16.
    Lefkowitz RJ. The superfamily of heptahelical receptors. Nat Cell Biol 2000;2:E133–36.PubMedCrossRefGoogle Scholar
  17. 17.
    Lefkowitz RJ. Historical review: a brief history and personal retrospective of seven-transmembrane receptors. Trends Pharmacol Sci 2004;25:413–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Lefkowitz RJ. Seven transmembrane receptors: a brief personal retrospective. Biochim Biophys Acta 2007;1768:748–55.PubMedCrossRefGoogle Scholar
  19. 19.
    Maggio R., Innamorati G., Parenti M. G protein-coupled receptor oligomerization provides the framework for signal discrimination. J Neurochem 2007;103:1741–52.PubMedCrossRefGoogle Scholar
  20. 20.
    Han DS, Wang SX, Weinstein H. Active state-like conformational elements in the beta(2)-AR and a photoactivated intermediate of rhodopsin identified by dynamic properties of GPCRs. Biochemistry 2008;47:7317–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Huang P, Li J, Chen CG, Visiers I, Weinstein H, Liu-Chen LY. Functional role of a conserved motif in TM6 of the rat mu opioid receptor: constitutively active and inactive receptors result from substitutions of Thr6.34(279) with Lys and Asp. Biochemistry 2001;40:13501–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Prioleau C, Visiers I, Ebersole BJ, Weinstein H, Sealfon SC. Conserved helix 7 tyrosine acts as a multistate conformational switch in the 5HT2C receptor – Identification of a novel "locked-on" phenotype and double revertant mutations. J Biol Chem 2002;277:36577–84.PubMedCrossRefGoogle Scholar
  23. 23.
    Visiers I, Ballesteros JA, Weinstein H. Three-dimensional representations of G protein-coupled receptor structures and mechanisms. G Protein Pathways, Pt a, Receptors 2002;343:329–71.CrossRefGoogle Scholar
  24. 24.
    Ballesteros JA, Jensen AD, Liapakis G, et al. Activation of the beta(2)-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J Biol Chem 2001;276:29171–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Konvicka K, Guarnieri F, Ballesteros JA, Weinstein H. Proposed structure for the NPxxY sequence motif in transmembrane segment 7 of G-protein coupled receptors. Biophys J 1997;72:A74.Google Scholar
  26. 26.
    Konvicka K, Guarnieri F, Ballesteros JA, Weinstein H. A proposed structure for transmembrane segment 7 of G protein-coupled receptors incorporating an Asn-Pro/Asp-Pro motif. Biophys J 1998;75:601–11.PubMedCrossRefGoogle Scholar
  27. 27.
    Bhattacharya M, Babwah AV, Ferguson SS. Small GTP-binding protein-coupled receptors. Biochem Soc Trans 2004;32:1040–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Bhattacharya S, Hall S, Vaidehi N. Agonist-induced conformational changes in Bovine rhodopsin: insight into activation of G-protein-coupled receptors. J Mol Biol 2008;382: 539–55.PubMedCrossRefGoogle Scholar
  29. 29.
    Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000;289:739–45.PubMedCrossRefGoogle Scholar
  30. 30.
    Day PW, Rasmussen SGF, Parnot C, et al. A monoclonal antibody for G protein-coupled receptor crystallography. Nature Methods 2007;4:927–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Rasmussen SGF, Choi HJ, Rosenbaum DM, et al. Crystal structure of the human beta(2) adrenergic G-protein-coupled receptor. Nature 2007;450:383–U4.PubMedCrossRefGoogle Scholar
  32. 32.
    Cherezov V, Rosenbaum DM, Hanson MA, et al. High-resolution crystal structure of an engineered human beta(2)-adrenergic G protein-coupled receptor. Science 2007;318:1258–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Rosenbaum DM, Cherezov V, Hanson MA, et al. GPCR engineering yields high-resolution structural insights into beta(2)-adrenergic receptor function. Science 2007;318:1266–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Warne T, Serrano-Vega MJ, Baker JG, et al. Structure of a beta(1)-adrenergic G-protein-coupled receptor. Nature 2008;454:486–491.PubMedCrossRefGoogle Scholar
  35. 35.
    Jaakola VP, Griffith MT, Hanson MA, et al. The 2.6 angstrom crystal structure of a human A(2A) adenosine receptor bound to an antagonist. Science 2008;322:1211–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Xhaard H, Rantanen VV, Nyronen T, Johnson MS. Molecular evolution of adrenoceptors and dopamine receptors: Implications for the binding of catecholamines. J Med Chem 2006;49:1706–19.PubMedCrossRefGoogle Scholar
  37. 37.
    Missale C, Nash R, Robinson S, Jaber M, Caron M. Dopamine receptors: from structure to function. Physiol Rev 1998;78:189–225.PubMedGoogle Scholar
  38. 38.
    Pivonello R, Ferone D, de Herder WW, et al. Dopamine receptor expression and function in corticotroph ectopic tumors. J Clin Endocrinol Metab 2007;92:65–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Thevenin D, Lazarova T. Stable interactions between the transmembrane domains of the adenosine A2A receptor. Protein Sci 2008;17:1188–99.PubMedCrossRefGoogle Scholar
  40. 40.
    Javitch JA. The ants go marching two by two: oligomeric structure of G-protein-coupled receptors. Mol Pharmacol 2004;66:1077–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Ballesteros J, Palczewski K. G protein-coupled receptor drug discovery: implications from the crystal structure of rhodopsin. Curr Opin Drug Discov Devel 2001;4:561–74.PubMedGoogle Scholar
  42. 42.
    Lefkowitz RJ. Seven transmembrane receptors: something old, something new. Acta Physiol 2007;190:9–19.CrossRefGoogle Scholar
  43. 43.
    Sansom MSP, Weinstein H. Hinges, swivels and switches: the role of prolines in signalling via transmembrane alpha-helices. Trends Pharmacol Sci 2000;21:445–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Visiers I, Ballesteros J, Weinstein H. A spatially ordered sequence of intramolecular rearrangements observed from simulations of agonist-related activation of 5HT(2C) receptors. Biophys J 2000;78:394Pos.Google Scholar
  45. 45.
    Ceruso MA, Weinstein H. Structural mimicry of proline kinks: tertiary packing interactions support local structural distortions. J Mol Biol 2002;318:1237–49.PubMedCrossRefGoogle Scholar
  46. 46.
    Shi L, Liapakis G, Xu R, Guarnieri F, Ballesteros JA, Javitch JA. Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J Biol Chem 2002;277:40989–96.PubMedCrossRefGoogle Scholar
  47. 47.
    Ballesteros JA, Deupi X, Olivella M, Haaksma EEJ, Pardo L. Serine and threonine residues bend alpha-helices in the chi(1) = g(–) conformation. Biophys J 2000;79:2754–60.PubMedCrossRefGoogle Scholar
  48. 48.
    Shi L, Simpson MM, Ballesteros JA, Javitch JA. The first transmembrane segment of the dopamine D2 receptor: accessibility in the binding-site crevice and position in the transmembrane bundle. Biochemistry 2001;40:12339–48.PubMedCrossRefGoogle Scholar
  49. 49.
    Liapakis G, Simpson MM, Javitch JA. The substituted-cysteine accessibility method (SCAM) to elucidate membrane protein structure. Curr Protoc Neurosci 2001;Chapter 4:Unit 4.15.PubMedGoogle Scholar
  50. 50.
    Hubbell WL, Altenbach C, Hubbell CM, Khorana HG, Douglas CR. Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide cross-linking. Adv Protein Chem 2003;63: 243–90.PubMedCrossRefGoogle Scholar
  51. 51.
    Shukla AK, Sun J-P, Lefkowitz RJ. Crystallizing thinking about the {beta}2-adrenergic receptor. Mol Pharmacol 2008;73:1333–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Kobilka BK, Deupi X. Conformational complexity of G-protein-coupled receptors. Trends Pharmacol Sci 2007;28:397–406.PubMedCrossRefGoogle Scholar
  53. 53.
    Schwartz TU, Schmidt D, Brohawn SG, Blobel G. Homodimerization of the G protein SRbeta in the nucleotide-free state involves proline cis/trans isomerization in the switch II region. Proc Natl Acad Sci U S A 2006;103:6823–8.PubMedCrossRefGoogle Scholar
  54. 54.
    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.PubMedCrossRefGoogle Scholar
  55. 55.
    Sheikh SP, Vilardarga JP, Baranski TJ, et al. Similar structures and shared switch mechanisms of the beta2-adrenoceptor and the parathyroid hormone receptor. Zn(II) bridges between helices III and VI block activation. The J Biol Chem 1999;274:17033–41.CrossRefGoogle Scholar
  56. 56.
    Binet V, Duthey BA, Lecaillon J, et al. Common structural requirements for heptahelical domain function in class A and class C GPCRS. J Biol Chem 2007.Google Scholar
  57. 57.
    Park PS, Lodowski DT, Palczewski K. Activation of G protein-coupled receptors: beyond two-state models and tertiary conformational changes. Ann Rev Pharmacol Toxicol 2008;48:107–41.CrossRefGoogle Scholar
  58. 58.
    Xu W, Li J, Chen CG, et al. Comparison of the amino acid residues in the sixth transmembrane domains accessible in the binding-site crevices of mu, delta, and kappa opioid receptors. Biochemistry 2001;40:8018–29.PubMedCrossRefGoogle Scholar
  59. 59.
    Javitch JA, Fu DY, Liapakis G, Chen JY. Constitutive activation of the beta(2) adrenergic receptor alters the orientation of its sixth membrane-spanning segment. J Biol Chem 1997;272:18546–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Bourne H. How receptors talk to trimeric G proteins. Curr Opin Cell Biol 1997;9:134–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Elling CE, Frimurer TM, Gerlach LO, Jorgensen R, Holst B, Schwartz TW. Metal ion site engineering indicates a global toggle switch model for seven-transmembrane receptor activation. J Biol Chem 2006;281:17337–46.PubMedCrossRefGoogle Scholar
  62. 62.
    Gether U, Ballesteros JA, Seifert R, SandersBush E, Weinstein H, Kobilka BK. Structural instability of a constitutively active G protein-coupled receptor – agonist-independent activation due to conformational flexibility. J Biol Chem 1997;272:2587–90.PubMedCrossRefGoogle Scholar
  63. 63.
    Li J, Huang P, Chen CG, de Riel JK, Weinstein H, Liu-Chen LY. Constitutive activation of the mu opioid receptor by mutation of D3.49(164), but not D3.32(147): D3.49(164) is critical for stabilization of the inactive form of the receptor and for its expression. Biochemistry 2001;40:12039–50.PubMedCrossRefGoogle Scholar
  64. 64.
    Rasmussen SGF, Jensen AD, Liapakis G, Ghanouni P, Javitch JA, Gether U. Mutation of a highly conserved aspartic acid in the beta(2) adrenergic receptor: constitutive activation, structural instability, and conformational rearrangement of transmembrane segment 6. Mol Pharmacol 1999;56:175–84.PubMedGoogle Scholar
  65. 65.
    Haydock K, Weinstein H. Molecular dynamics simulations to model the properties of constitutively active GPCR mutants. Biophys J 1995;68:A255.Google Scholar
  66. 66.
    Cotecchia S. Constitutive activity and inverse agonism at the alpha1adrenoceptors. Biochem Pharmacol 2007;73:1076–83.PubMedCrossRefGoogle Scholar
  67. 67.
    Cotecchia S, Exum S, Caron MG, Lefkowitz RJ. Regions of the alpha 1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. Proc Natl Acad Sci U S A 1990;87:2896–900.PubMedCrossRefGoogle Scholar
  68. 68.
    Gether U, Lin S, Ghanouni P, Ballesteros JA, Weinstein H, Kobilka BK. Agonists induce conformational changes in transmembrane domains III and VI of the beta(2) adrenoceptor. Embo J 1997;16:6737–47.PubMedCrossRefGoogle Scholar
  69. 69.
    Parnot C. Systematic identification of mutations that constitutively activate the angiotensin II type 1A receptor by screening a randomly mutated cDNA library with an original pharmacological bioassay. Proc Natl Acad Sci USA 2000;97:7615–20.PubMedCrossRefGoogle Scholar
  70. 70.
    Parnot C, Miserey-Lenkei S, Bardin S, Corvol P, Clauser E. Lessons from constitutively active mutants of G protein-coupled receptors. Trends Endocrinol Metab 2002;13: 336–43.PubMedCrossRefGoogle Scholar
  71. 71.
    Ballesteros J, Kitanovic S, Guarnieri F, et al. Functional microdomains in g-protein-coupled receptors – the conserved Arginine-cage motif in the gonadotropin-releasing hormone receptor. J Biol Chem 1998;273:10445–53.PubMedCrossRefGoogle Scholar
  72. 72.
    Ballesteros JA, Kitanovic S, Guarnieri F et al. Functional microdomains in G protein-coupled receptors: the conserved arginine cage motif in the gonadotropin-releasing hormone receptor. J Biol Chem 1998;273:10445–53.PubMedCrossRefGoogle Scholar
  73. 73.
    Shapiro DA, Kristiansen K, Weiner DM, Kroeze WK, Roth BL. Evidence for a model of agonist-induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6. J Biol Chem 2002;277:11441–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Huang P, Visiers I, Weinstein H, Liu-Chen LY. The local environment at the cytoplasmic end of TM6 of the mu opioid receptor differs from those of rhodopsin and monoamine receptors: Introduction of an ionic lock between the cytoplasmic ends of helices 3 and 6 by a L6.30(275)E mutation inactivates the mu opioid receptor and reduces the constitutive activity of its T6.34(279)K mutant. Biochemistry 2002;41:11972–80.PubMedCrossRefGoogle Scholar
  75. 75.
    Dror RO, Arlow DH, Borhani DW, Jensen Mo, Piana S, Shaw DE. Identification of two distinct inactive conformations of the (beta)2-adrenergic receptor reconciles structural and biochemical observations. Proc Natl Acad Sci U S A 2009 – Available Online.Google Scholar
  76. 76.
    Kobilka BK. G protein coupled receptor structure and activation. Biochim Biophys Acta 2007;1768:794–807.CrossRefPubMedGoogle Scholar
  77. 77.
    Kobilka B, Schertler GF. New G-protein-coupled receptor crystal structures: insights and limitations. Trends Pharmacol Sci 2008;29:79–83.PubMedCrossRefGoogle Scholar
  78. 78.
    Neve KA, Cox BA, Henningsen RA, Spanoyannis A, Neve RL. Pivotal role for aspartate-80 in the regulation of dopamine D2 receptor affinity for drugs and inhibition of adenylyl cyclase. Mol Pharmacol 1991;39:733–9.PubMedGoogle Scholar
  79. 79.
    Neve KA, Cumbay MG, Thompson KR, Yang R, Buck DC. Modeling and mutational analysis of a putative sodium-binding pocket on the dopamine D2 receptor. Mol Pharmacol 2001;60:373.PubMedGoogle Scholar
  80. 80.
    Mansour A, Meng F, Meador-Woodruff JH, Taylor LP, Civelli O, Akil H. Site-directed mutagenesis of the human dopamine D2 receptor. Eur J Pharmacol 1992;227:205–14.PubMedCrossRefGoogle Scholar
  81. 81.
    Javitch JA. Mapping the binding-site crevice of the D2 receptor. Adv Pharmacol 1998;42:412–5.PubMedCrossRefGoogle Scholar
  82. 82.
    Javitch JA. Probing structure of neurotransmitter transporters by substituted-cysteine accessibility method. Neurotransmitter Transporters 1998;296:331–46.CrossRefGoogle Scholar
  83. 83.
    Javitch JA, Ballesteros JA, Chen JY, Chiappa V, Simpson MM. Electrostatic and aromatic microdomains within the binding-site crevice of the D2 receptor: contributions of the second membrane-spanning segment. Biochemistry 1999;38:7961–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Javitch JA, Ballesteros JA, Weinstein H, Chen J. A cluster of aromatic residues in the sixth membrane-spanning segment of the dopamine D2 receptor is accessible in the binding-site crevice. Biochemistry 1998;37:998–1006.PubMedCrossRefGoogle Scholar
  85. 85.
    Javitch JA, Fu D, Chen J. Residues in the fifth membrane-spanning segment of the dopamine D2 receptor exposed in the binding-site crevice. Biochemistry 1995;34:16433–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Javitch JA, Fu D, Chen J, Karlin A. Mapping the binding-site crevice of the dopamine D2 receptor by the substituted-cysteine accessibility method. Neuron 1995;14:825–31.PubMedCrossRefGoogle Scholar
  87. 87.
    Javitch JA, Fu DY, Chen JY. Differentiating dopamine D-2 ligands by their sensitivities to modification of the cysteine exposed in the binding-site crevice. Mol Pharmacol 1996;49:692–8.PubMedGoogle Scholar
  88. 88.
    Javitch JA, Li X, Kaback J, Karlin A. A cysteine residue in the third membrane-spanning segment of the human D2 dopamine receptor is exposed in the binding-site crevice. Proc Natl Acad Sci U S A 1994;91:10355–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Javitch JA, Shi L, Simpson MM, Chen J, Chiappa V. The fourth transmembrane segment of the dopamine D2 receptor: accessibility in the binding-site crevice and position in the transmembrane bundle. Biochemistry 2000;39:12,190.Google Scholar
  90. 90.
    Fu DY, Ballesteros JA, Weinstein H, Chen JY, Javitch JA. Residues in the seventh membrane-spanning segment of the dopamine D2 receptor accessible in the binding-site crevice. Biochemistry 1996;35:11278–85.PubMedCrossRefGoogle Scholar
  91. 91.
    Simpson MM, Ballesteros JA, Chiappa V, et al. Dopamine D4/D2 receptor selectivity is determined by a divergent aromatic microdomain contained within the second, third, and seventh membrane-spanning segments. Mol Pharmacol 1999;56:1116–26.PubMedGoogle Scholar
  92. 92.
    Coley C, Woodward R, Johansson AM, Strange PG, Naylor LH. Effect of multiple serine/alanine mutations in the transmembrane spanning region V of the D2 dopamine receptor on ligand binding. Journal of neurochemistry 2000;74:358–66.PubMedCrossRefGoogle Scholar
  93. 93.
    Ericksen SS, Cummings DF, Weinstein H, Schetz JA. Ligand selectivity of D-2 dopamine receptors is modulated by changes in local dynamics produced by sodium binding. J Pharmacol Exp Thers 2009;328:40–54.CrossRefGoogle Scholar
  94. 94.
    Schetz JA, Benjamin PS, Sibley DR. Nonconserved residues in the second transmembrane-spanning domain of the D4 dopamine receptor are molecular determinants of D4-selective pharmacology. Mol Pharmacol 2000;57:144–52.PubMedGoogle Scholar
  95. 95.
    Schetz JA, Sibley DR. Tandem sulfur-containing amino acids are epicritical determinants of dopamine D(2) receptor pharmacology. Eur J Pharmacol 2000;388:R5–R7.PubMedCrossRefGoogle Scholar
  96. 96.
    Neve KA. Regulation of dopamine D2 receptors by sodium and pH. Mol Pharmacol 1991;39:570.PubMedGoogle Scholar
  97. 97.
    Kortagere S, Gmeiner P, Weinstein H, Schetz JA. Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain. Mol Pharmacol 2004;66:1491–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Ortore G, Tuccinardi T, Bertini S, Martinelli A. A theoretical study to investigate D2DAR/D4DAR selectivity; receptor modeling and molecular docking of dopaminergic ligands. J Med Chem 2006;49:1397–407.PubMedCrossRefGoogle Scholar
  99. 99.
    Mehler EL, Hassan SA, Kortagere S, Weinstein H. Ab initio computational modeling of loops in G-protein-coupled receptors: lessons from the crystal structure of rhodopsin. Proteins 2006;64:673–90.PubMedCrossRefGoogle Scholar
  100. 100.
    Mehler EL, Periole X, Hassan SA, Weinstein H. Key issues in the computational simulation of GPCR function: representation of loop domains. J Comput Aided Mol Des 2002;15:13.Google Scholar
  101. 101.
    Christopoulos A, Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol Rev 2002;54:323–74.PubMedCrossRefGoogle Scholar
  102. 102.
    de Graaf C, Foata N, Engkvist O, Rognan D. Molecular modeling of the second extracellular loop of G-protein coupled receptors and its implication on structure-based virtual screening. Proteins 2008;71:599–620.PubMedCrossRefGoogle Scholar
  103. 103.
    Karnik S, Gogonea C, Patil S, Saad Y, Takezako T. Activation of G-protein-coupled receptors: a common molecular mechanism. Trends Endocrinol Metabol 2003;14: 431–7.CrossRefGoogle Scholar
  104. 104.
    Savarese TM, Wang CD, Fraser CM. Site-directed mutagenesis of the rat m1 muscarinic acetylcholine receptor. Role of conserved cysteines in receptor function. J Biol Chem 1992;267:11439–48.PubMedGoogle Scholar
  105. 105.
    Zeng FY, Soldner A, Schoneberg T, Wess J. Conserved extracellular cysteine pair in the M3 muscarinic acetylcholine receptor is essential for proper receptor cell surface localization but not for G protein coupling. J Neurochem 1999;72:2404–14.PubMedCrossRefGoogle Scholar
  106. 106.
    Noda K, Saad Y, Graham RM, Karnik SS. The high affinity state of the beta 2-adrenergic receptor requires unique interaction between conserved and non-conserved extracellular loop cysteines. J Biol Chem 1994;269:6743.PubMedGoogle Scholar
  107. 107.
    Lin S, Gether U, Kobilka BK. Ligand stabilization of the beta 2 adrenergic receptor: effect of DTT on receptor conformation monitored by circular dichroism and fluorescence spectroscopy. Biochemistry 1996;35:14,445.Google Scholar
  108. 108.
    Scarselli M, Li B, Kim SK, Wess J. Multiple residues in the second extracellular loop are critical for M3 muscarinic acetylcholine receptor activation. J Biol Chem 2007;282:7385–96.PubMedCrossRefGoogle Scholar
  109. 109.
    Zhao MM, Hwa J, Perez DM. Identification of critical extracellular loop residues involved in alpha 1-adrenergic receptor subtype-selective antagonist binding. Mol Pharmacol 1996;50:1118.PubMedGoogle Scholar
  110. 110.
    Wurch T, Pauwels PJ. Coupling of canine serotonin 5-HT(1B) and 5-HT(1D) receptor subtypes to the formation of inositol phosphates by dual interactions with endogenous G(i/o) and recombinant G(alpha15) proteins. J Neurochem 2000;75:1180.PubMedCrossRefGoogle Scholar
  111. 111.
    Wurch T, Colpaert FC, Pauwels PJ. Chimeric receptor analysis of the ketanserin binding site in the human 5-hydroxytryptamine1D receptor: importance of the second extracellular loop and fifth transmembrane domain in antagonist binding. Mol Pharmacol 1998;54:1088.PubMedGoogle Scholar
  112. 112.
    Menon S, Han M, Sakmar T. Rhodopsin: Structural basis of molecular physiology. Physiol Rev 2001;81:1659–88.PubMedGoogle Scholar
  113. 113.
    Bourne HR, Meng EC. Structure. Rhodopsin sees the light. Science 2000;289:733.PubMedCrossRefGoogle Scholar
  114. 114.
    Shi L, Javitch JA. The binding site of aminergic G protein-coupled receptors: the transmembrane segments and second extracellular loop. Annu Rev Pharmacol Toxicol 2002;42: 437–67.PubMedCrossRefGoogle Scholar
  115. 115.
    Shi L, Javitch JA. The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice. Proc Natl Acad Sci U S A 2004;101:440–5.PubMedCrossRefGoogle Scholar
  116. 116.
    Conner M, Hawtin SR, Simms J, et al. Systematic analysis of the entire second extracellular loop of the V1a vasopressin receptor: key residues, conserved throughout a G-protein-coupled receptor family, identified. J Biol Chem 2007;282:17405–12 .PubMedCrossRefGoogle Scholar
  117. 117.
    Baneres JL, Mesnier D, Martin A, Joubert L, Dumuis A, Bockaert J. Molecular characterization of a purified 5-HT4 receptor: a structural basis for drug efficacy. J Biol Chem 2005;280:20253–60.PubMedCrossRefGoogle Scholar
  118. 118.
    Kleinau G, Jaeschke H, Mueller S, Worth CL, Paschke R, Krause G. Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR. Cell Mol Life Sci 2008;65:3664–76.PubMedCrossRefGoogle Scholar
  119. 119.
    White J, Grodnitzky J, Louis J, et al. Dimerization of the class A G protein-coupled neurotensin receptor NTS1 alters G protein interaction. Proc Natl Acad Sci U S A 2007;104:12199–204.PubMedCrossRefGoogle Scholar
  120. 120.
    Mowbray SL, Petsko GA. The x-ray structure of the periplasmic galactose binding protein from Salmonella typhimurium at 3.0-A resolution. J Biol Chem 1983;258:7991–7.PubMedGoogle Scholar
  121. 121.
    Okamoto T, Sekiyama N, Otsu M, et al. Expression and purification of the extracellular ligand binding region of metabotropic glutamate receptor subtype 1. J Biol Chem 1998;273:13089–96.PubMedCrossRefGoogle Scholar
  122. 122.
    Chabre M, Lemaire M. Monomeric G-protein-coupled receptor as a functional unit. Biochemistry 2005;44:9395–403.PubMedCrossRefGoogle Scholar
  123. 123.
    Meyer B, Segura J-M, Martinez K, et al. FRET imaging reveals that functional neurokinin-1 receptors are monomeric and reside in membrane microdomains of live cells. Proc Natl Acad Sci U S A 2006;103:2138–43.PubMedCrossRefGoogle Scholar
  124. 124.
    Overton M, Blumer K. Use of fluorescence resonance energy transfer to analyze oligomerization of G-protein-coupled receptors expressed in yeast. Methods 2002;27:324–32.PubMedCrossRefGoogle Scholar
  125. 125.
    Overton MC, Blumer KJ. G-protein-coupled receptors function as oligomers in vivo. Curr Biol 2000;10:341–4.PubMedCrossRefGoogle Scholar
  126. 126.
    Overton MC, Blumer KJ. The extracellular N-terminal domain and transmembrane domains 1 and 2 mediate oligomerization of a yeast G protein-coupled receptor. J Biol Chem 2002;277:41463–72.PubMedCrossRefGoogle Scholar
  127. 127.
    Overton MC, Chinault SL, Blumer KJ. Oligomerization, biogenesis, and signaling is promoted by a glycophorin A-like dimerization motif in transmembrane domain 1 of a yeast G protein-coupled receptor. J Biol Chem 2003;278:49369–77.PubMedCrossRefGoogle Scholar
  128. 128.
    Overton MC, Chinault SL, Blumer KJ. Oligomerization of G-protein-coupled receptors: lessons from the yeast Saccharomyces cerevisiae. Eukaryot Cell 2005;4:1963–70.PubMedCrossRefGoogle Scholar
  129. 129.
    Canals M, Lopez-Gimenez JF, Milligan G. Cell surface delivery and structural re-organization by pharmacological chaperones of an oligomerization-defective alpha(1b)-adrenoceptor mutant demonstrates membrane targeting of GPCR oligomers. Biochemical J 2009;417:161–72.CrossRefGoogle Scholar
  130. 130.
    Carrillo JJ, Lopez-Gimenez JF, Milligan G. Multiple interactions between transmembrane helices generate the oligomeric {alpha}1b-Adrenoceptor. Mol Pharmacol 2004;66:1123–37.PubMedCrossRefGoogle Scholar
  131. 131.
    Fredholm BB, Hokfelt T, Milligan G. G-protein-coupled receptors: an update. Acta Physiol 2007;190:3–7.CrossRefGoogle Scholar
  132. 132.
    Lopez-Gimenez JF, Canals M, Pediani JD, Milligan G. The {alpha}1b-adrenoceptor exists as a higher-order oligomer: effective oligomerization is required for receptor maturation, surface delivery, and function. Mol Pharmacol 2007;71:1015–29.PubMedCrossRefGoogle Scholar
  133. 133.
    Milligan G. Oligomerisation of G-protein-coupled receptors. J Cell Sci 2001;114:1265–71.PubMedGoogle Scholar
  134. 134.
    Milligan G. G protein-coupled receptor dimerization: function and ligand pharmacology. Mol Pharmacol 2004;66:1–7.PubMedCrossRefGoogle Scholar
  135. 135.
    Milligan G. GPCR dimerisation: molecular basis and relevance for function and pharmacology. Biochim Biophys Acta 2007;1768:825–35.Google Scholar
  136. 136.
    Milligan G, Anonymous, Behan D, inventors; The University Court of the University of Glasgow, assignee. Materials and methods relating to G-protein coupled receptor oligomers patent US 07405053. 2008.Google Scholar
  137. 137.
    Milligan G, Ramsay D, Pascal G, Carrillo JJ. GPCR dimerisation. Life sciences 2003;74:181–8.PubMedCrossRefGoogle Scholar
  138. 138.
    Skrabanek L, Murcia M, Bouvier M, et al. Requirements and ontology for a G protein-coupled receptor oligomerization knowledge base. BMC Bioinformatics 2007;8:177.PubMedCrossRefGoogle Scholar
  139. 139.
    Filizola M, Guo W, Javitch JA, Weinstein H. Dimerization in G-protein coupled receptors: correlation analysis and electron density maps of rhodopsin from different species suggest subtype-specific interfaces. Biophys J 2003;84:269A-70A.Google Scholar
  140. 140.
    Filizola M, Olmea O, Weinstein H. Using correlated mutation analysis to predict the heterodimerization interface of GPCRs. Biophys J 2002;82:2307.Google Scholar
  141. 141.
    Filizola M, Wang S, Weinstein H. Dynamic models of G-protein coupled receptor dimers: indications of asymmetry in the rhodopsin dimer from molecular dynamics simulations in a POPC bilayer. J Comput Aided Mol Des 2006;20, 405–416.PubMedCrossRefGoogle Scholar
  142. 142.
    Filizola M, Weinstein H. Structural models for dimerization of G-protein coupled receptors: the opioid receptor homodimers. Biopolymers 2002;66:317–25.PubMedCrossRefGoogle Scholar
  143. 143.
    Filizola M, Weinstein H. The structure and dynamics of GPCR oligomers: a new focus in models of cell-signaling mechanisms and drug design. Curr Opin Drug Discov Devel 2005;8:577–84.PubMedGoogle Scholar
  144. 144.
    Filizola M, Weinstein H. The study of G-protein coupled receptor oligomerization with computational modeling and bioinformatics. FEBS J 2005;272:2926–38.PubMedCrossRefGoogle Scholar
  145. 145.
    Guo W, Shi L, Filizola M, Weinstein H, Javitch J. From the cover: Crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc Natl Acad Sci U S A 2005;102:17495–500.PubMedCrossRefGoogle Scholar
  146. 146.
    Wang XS, Filizola M, Ceruso M, Weinstein H. Rhodopsin dimers: molecular dynamics simulations using discrete representations of the membrane and water environment. Biophys J 2005;88:81A-A.Google Scholar
  147. 147.
    Guo W, Urizar E, Kralikova M, et al. Dopamine D2 receptors form higher order oligomers at physiological expression levels. Embo J 2008;27:2293–304.PubMedCrossRefGoogle Scholar
  148. 148.
    Hastrup H, Karlin A, Javitch JA. Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment. Proc Natl Acad Sci U S A 2001;98:10055–60.PubMedCrossRefGoogle Scholar
  149. 149.
    McVey M, Ramsay D, Kellett E, et al. Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer – The human delta-opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy. J Biol Chem 2001;276:14092–9.PubMedGoogle Scholar
  150. 150.
    Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K. Atomic-force microscopy: rhodopsin dimers in native disc membranes. Nature 2003;421:127–8.PubMedCrossRefGoogle Scholar
  151. 151.
    Fotiadis D, Jastrzebska B, Philippsen A, Muller D, Palczewski K, Engel A. Structure of the rhodopsin dimer: a working model for G-protein-coupled receptors. Theory and simulation/Macromolecular assemblages – Joel Janin and Michael Levitt/Edward H Egelman and Andrew GW Leslie 2006;16:252–9.Google Scholar
  152. 152.
    Strange P. Oligomers of D2 dopamine receptors: evidence from ligand binding. J Mol Neurosci2005;26:155–60.PubMedCrossRefGoogle Scholar
  153. 153.
    Park P, Sum CS, Hampson DR, Van Tol HHM, Wells JW. Nature of the oligomers formed by muscarinic m2 acetylcholine receptors in Sf9 cells. Eur J Pharmacol 2001;421: 11–22.PubMedCrossRefGoogle Scholar
  154. 154.
    Park PSH, Filipek S, Wells JW, Palczewski K. Oligomerization of G protein-coupled receptors: Past, present, and future. Biochemistry 2004;43:15643–56.PubMedCrossRefGoogle Scholar
  155. 155.
    Paul S.-H. Park JWW. Oligomeric potential of the M2 muscarinic cholinergic receptor. J Neurochem 2004;90:537–48.CrossRefGoogle Scholar
  156. 156.
    Pin JP, Neubig R, Bouvier M, et al. International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacol Rev 2007;59:5–13.PubMedCrossRefGoogle Scholar
  157. 157.
    Bartfai T, Benovic JL, Bockaert J, et al. The state of GPCR research in 2004. Nat Rev Drug Discov 2004;3:574–626.Google Scholar
  158. 158.
    Maggio R, Novi F, Scarselli M, Corsini GU. The impact of G-protein-coupled receptor hetero-oligomerization on function and pharmacology. FEBS J 2005;272:2939–46.PubMedCrossRefGoogle Scholar
  159. 159.
    Prinster S, Hague C, Hall R. Heterodimerization of G protein-coupled receptors: specificity and functional significance. Pharmacol Rev 2005;57:289–98.PubMedCrossRefGoogle Scholar
  160. 160.
    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. The J Biol Chem 2003;278:21655–62.CrossRefGoogle Scholar
  161. 161.
    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;282:19203–16.PubMedCrossRefGoogle Scholar
  162. 162.
    Breitwieser GE. G protein-coupled receptor oligomerization: implications for G protein activation and cell signaling. Circ Res 2004;94:17–27.PubMedCrossRefGoogle Scholar
  163. 163.
    Lee SP, So CH, Rashid AJ, et al. Dopamine D1 and D2 receptor co-activation generates a novel phospholipase C-mediated calcium signal. The J Biol Chem 2004;279:35671–8.CrossRefGoogle Scholar
  164. 164.
    Rashid AJ, So CH, Kong MM, et al. D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci U S A 2007;104:654–9.PubMedCrossRefGoogle Scholar
  165. 165.
    O‘Dowd BF, Ji X, Alijaniaram M, et al. Dopamine receptor oligomerization visualized in living cells. J Biol Chem 2005;280:37225–35.PubMedCrossRefGoogle Scholar
  166. 166.
    Dziedzicka-Wasylewska M, Faron-Gorecka A, Andrecka J, Polit A, Kusmider M, Wasylewski Z. Fluorescence studies reveal heterodimerization of dopamine D1 and D2 receptors in the plasma membrane. Biochemistry 2006;45:8751–9.PubMedCrossRefGoogle Scholar
  167. 167.
    So CH, Varghese G, Curley KJ, et al. D1 and D2 dopamine receptors form heterooligomers and cointernalize after selective activation of either receptor. Mol Pharmacol 2005;68:568–78.PubMedGoogle Scholar
  168. 168.
    So CH, Verma V, O‘Dowd BF, George SR. Desensitization of the dopamine D1 and D2 receptor hetero-oligomer mediated calcium signal by agonist occupancy of either receptor. Mol Pharmacol 2007;72:450–62.PubMedCrossRefGoogle Scholar
  169. 169.
    Kong MMC, Fan T, Varghese G, O‘Dowd BF, George SR. Agonist-induced cell surface trafficking of an intracellularly sequestered D1 dopamine receptor homo-oligomer. Mol Pharmacol 2006;70:78–89.PubMedGoogle Scholar
  170. 170.
    Milligan G. G-protein-coupled receptor heterodimers: pharmacology, function and relevance to drug discovery. Drug Discov Today 2006;11:541–9.PubMedCrossRefGoogle Scholar
  171. 171.
    Mannoury la Cour C, Vidal S, Pasteau V, Cussac D, Millan MJ. Dopamine D1 receptor coupling to Gs/olf and Gq in rat striatum and cortex: A scintillation proximity assay (SPA)/antibody-capture characterization of benzazepine agonists. Neuropharmacology 2007;52:1003–14.PubMedCrossRefGoogle Scholar
  172. 172.
    Jin LQ, Wang HY, Friedman E. Stimulated D-1 dopamine receptors couple to multiple G alpha proteins in different brain regions. J Neurochem 2001;78:981–90.PubMedCrossRefGoogle Scholar
  173. 173.
    Ming YL, Zhang H, Long LH, Wang F, Chen JG, Zhen XC. Modulation of Ca2+ signals by phosphatidylinositol-linked novel D1 dopamine receptor in hippocampal neurons. J Neurochem 2006;98:1316–23.PubMedCrossRefGoogle Scholar
  174. 174.
    Ali MK, Bergson C. Elevated intracellular calcium triggers recruitment of the receptor cross-talk accessory protein calcyon to the plasma membrane. J Biol Chem 2003;278:51654–63.PubMedCrossRefGoogle Scholar
  175. 175.
    Lidow MS, Roberts A, Zhang L, Koh PO, Lezcano N, Bergson C. Receptor crosstalk protein, calcyon, regulates affinity state of dopamine D1 receptors. Eur J Pharmacol 2001;427:187–93.PubMedCrossRefGoogle Scholar
  176. 176.
    Novi F, Millan MJ, Corsini GU, Maggio R. Partial agonist actions of aripiprazole and the candidate antipsychotics S33592, bifeprunox, N-desmethylclozapine and preclamol at dopamine D-2L receptors are modified by co-transfection of D-3 receptors: potential role of heterodimer fort-nation. J Neurochem 2007;102:1410–24.PubMedCrossRefGoogle Scholar
  177. 177.
    Scarselli M, Novi F, Schallmach E, et al. D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J Biol Chem 2001;276:30308–14.PubMedCrossRefGoogle Scholar
  178. 178.
    Bolan EA, Kivell B, Jaligam V, et al. D2 receptors regulate dopamine transporter function via an ERK 1/2-dependent and PI3 kinase-independent mechanism. Mol Pharmacol 2007;71:1222–32.PubMedCrossRefGoogle Scholar
  179. 179.
    Lee F, Pei L, Moszczynska A, Vukusic B, Fletcher P, Liu F. Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor. The Embo J 2007;26:10.Google Scholar
  180. 180.
    Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 2000;288:154–7.PubMedCrossRefGoogle Scholar
  181. 181.
    Hillion J, Canals M, Torvinen M, et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 2002;277:18091–7.PubMedCrossRefGoogle Scholar
  182. 182.
    Kamiya T, Saitoh O, Yoshioka K, Nakata H. Oligomerization of adenosine A(2A) and dopamine D-2 receptors in living cells. Biochem Biophys Res Commun 2003;306:544–9.PubMedCrossRefGoogle Scholar
  183. 183.
    Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol 2005;67:1697–704.PubMedCrossRefGoogle Scholar
  184. 184.
    Pin JP, Galvez T, Prezeau L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther 2003;98:325–54.PubMedCrossRefGoogle Scholar
  185. 185.
    Damian M, Martin A, Mesnier D, Pin JP, Baneres JL. Asymmetric conformational changes in a GPCR dimer controlled by G-proteins. Embo J 2006;25:5693–702.PubMedCrossRefGoogle Scholar
  186. 186.
    Hlavackova V, Goudet C, Kniazeff J, et al. Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR. Embo J 2005;24:499–509.PubMedCrossRefGoogle Scholar
  187. 187.
    Kniazeff J, Bessis AS, Maurel D, Ansanay H, Prezeau L, Pin JP. Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nature Struct Mol Biol2004;11:706–13.CrossRefGoogle Scholar
  188. 188.
    Chandrashekar J, Hoon MA, Ryba NJP, Zuker CS. The receptors and cells for mammalian taste. Nature 2006;444:288–94.PubMedCrossRefGoogle Scholar
  189. 189.
    Springael JY, Urizar E, Costagliola S, Vassart G, Parmentier M. Allosteric properties of G protein-coupled receptor oligomers. Pharmacol Ther 2007;115:410–8.PubMedCrossRefGoogle Scholar
  190. 190.
    El Asmar L, Springael JY, Ballet S, Andrieu EU, Vassart G, Parmentier M. Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers. Mol Pharmacol 2005;67:460–9.PubMedCrossRefGoogle Scholar
  191. 191.
    Sohy D, Parmentier M, Springael JY. Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers. J Biol Chem 2007;282:30062–9.PubMedCrossRefGoogle Scholar
  192. 192.
    Springael JY, Le Minh PN, Urizar E, Costagliola S, Vassart G, Parmentier M. Allosteric modulation of binding properties between units of chemokine receptor homo- and hetero-oligomers. Mol Pharmacol 2006;69:1652–61.PubMedCrossRefGoogle Scholar
  193. 193.
    Waldhoer M, Fong J, Jones RM, et al. A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci U S A 2005;102:9050–5.PubMedCrossRefGoogle Scholar
  194. 194.
    Daniels DJ, Lenard NR, Etienne CL, Law PY, Roerig SC, Portoghese PS. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci U S A 2005;102:19208–13.PubMedCrossRefGoogle Scholar
  195. 195.
    Breit A, Gagnidze K, Devi LA, Lagace M, Bouvier M. Simultaneous activation of the {delta} Opioid Receptor ({delta}OR)/Sensory Neuron-Specific Receptor-4 (SNSR-4) Hetero-Oligomer by the mixed bivalent agonist bovine adrenal medulla peptide 22 activates SNSR-4 but inhibits {delta}OR signaling. Mol Pharmacol 2006;70:686–96.PubMedCrossRefGoogle Scholar
  196. 196.
    Park PSH, Palczewski K. Diversifying the repertoire of G protein-coupled receptors through oligomerization. Proc Natl Acad Sci U S A 2005;102:8793–4.PubMedCrossRefGoogle Scholar
  197. 197.
    Maggio R, Vogel Z, Wess J. Coexpression studies with mutant muscarinic adrenergic-receptors provide evidence for intermolecular cross-talk between G-protein-linked receptors. Proc Natl Acad Sci U S A 1993;90:3103–7.PubMedCrossRefGoogle Scholar
  198. 198.
    Hadac EM, Ji ZS, Pinon DI, Henne RM, Lybrand TP, Miller LJ. A peptide agonist acts by occupation of a monomeric G protein-coupled receptor: Dual sites of covalent attachment to domains near TM1 and TM7 of the same molecule make biologically significant domain-swapped dimerization unlikely. J Med Chem 1999;42:2105–11.PubMedCrossRefGoogle Scholar
  199. 199.
    Osuga Y, Hayashi M, Kudo M, Conti M, Kobilka B, Hsueh AJW. Co-expression of defective luteinizing hormone receptor fragments partially reconstitutes ligand-induced signal generation. J Biol Chem 1997;272:25006–12.PubMedCrossRefGoogle Scholar
  200. 200.
    Urizar E, Montanelli L, Loy T, et al. Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity. Embo J 2005;24:1954–64.PubMedCrossRefGoogle Scholar
  201. 201.
    Ji I, Lee C, Jeoung M, Koo Y, Sievert GA, Ji TH. Trans-activation of mutant follicle-stimulating hormone receptors selectively generates only one of two hormone signals. Mol Endocrinol 2004;18:968–78.PubMedCrossRefGoogle Scholar
  202. 202.
    Whorton MR, Bokoch MP, Rasmussen SGF, et al. A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc Natl Acad Sci U S A 2007;104:7682–7.PubMedCrossRefGoogle Scholar
  203. 203.
    Bayburt TH, Leitz AJ, Xie G, Oprian DD, Sligar SG. Transducin activation by nanoscale lipid bilayers containing one and two rhodopsins. J Biol Chem 2007;282:14875–81.PubMedCrossRefGoogle Scholar
  204. 204.
    Ernst OP, Gramse V, Kolbe M, Hofmann KP, Heck M. Monomeric G protein-coupled receptor rhodopsin in solution activates its G protein transducin at the diffusion limit. Proc Natl Acad Sci U S A 2007;104:10859–64.PubMedCrossRefGoogle Scholar
  205. 205.
    Galvez T. Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function. EMBO J 2001;20:2152–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Guo W, Shi L, Javitch JA. The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer. J Biol Chem 2003;278:4385–8.PubMedCrossRefGoogle Scholar
  207. 207.
    Salom D, Le Trong I, Pohl E, et al. Improvements in G protein-coupled receptor purification yield light stable rhodopsin crystals. J Struct Biol 2006;156:497–504.Google Scholar
  208. 208.
    Salom D, Lodowski DT, Stenkamp RE, et al. Crystal structure of a photoactivated deprotonated intermediate of rhodopsin. Proc Natl Acad Sci U S A 2006;103(44):16123–8.PubMedCrossRefGoogle Scholar
  209. 209.
    Taylor Ds, Fung HK, Rajgaria R, et al. Mutations affecting the oligomerization interface of G–protein–coupled receptors revealed by a novel denovo protein design framework. Biophys J 2008;94:2470–81.Google Scholar
  210. 210.
    Vohra S, Chintapalli SV, Illingworth CJR, et al. Computational studies of family a and family B GPCRs. Biochem Soc Trans 2007;35:749–54.PubMedCrossRefGoogle Scholar
  211. 211.
    Hebert TE, Moffett S, Morello JP, et al. A peptide derived from a beta(2)-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J Biol Chem 1996;271:16384–92.PubMedCrossRefGoogle Scholar
  212. 212.
    Harikumar K, Pinon D, Miller L. Transmembrane segment IV contributes a functionally important interface for oligomerization of the Class II G protein-coupled secretin receptor. J Biol Chem 2007;282:30363–72.PubMedCrossRefGoogle Scholar
  213. 213.
    Gouldson PR, Reynolds CA. Simulations on dimeric peptides: evidence for domain swapping in G-protein-coupled receptors? Biochem Soc Trans 1997;25:1066–71.PubMedGoogle Scholar
  214. 214.
    Gouldson PR, Snell CR, Bywater RP, Higgs C, Reynolds CA. Domain swapping in G-protein coupled receptor dimers. Protein Eng 1998;11:1181–93.PubMedCrossRefGoogle Scholar
  215. 215.
    Gouldson PR, Snell CR, Reynolds CA. A new approach to docking in the beta(2)-adrenergic receptor that exploits the domain structure of G-protein-coupled receptors. J Med Chem 1997;40:3871–86.PubMedCrossRefGoogle Scholar
  216. 216.
    Maggio R, Vogel Z, Wess J. Reconstitution of functional muscarinic receptors by coexpression of amino-terminal and carboxyl-terminal receptor fragments. FEBS Lett 1993;319: 195–200.PubMedCrossRefGoogle Scholar
  217. 217.
    Stanasila L, Perez J-B, Vogel H, Cotecchia S. Oligomerization of the {alpha}1a- and {alpha}1b-Adrenergic Receptor Subtypes: potential implications in receptor internalization. J Biol Chem 2003;278:40239–51.PubMedCrossRefGoogle Scholar
  218. 218.
    Hernanz-Falcon P, Rodriguez-Frade JM, Serrano A, et al. Identification of amino acid residues crucial for chemokine receptor dimerization. Nat Immunol 2004;5:216–23.PubMedCrossRefGoogle Scholar
  219. 219.
    Klco JM, Lassere TB, Baranski TJ. C5a receptor oligomerization – I. Disulfide trapping reveals oligomers and potential contact surfaces in a G protein-coupled receptor. J Biol Chem 2003;278:35345–53.PubMedCrossRefGoogle Scholar
  220. 220.
    Damien T, Tzvetana LMF, R. RCR. Oligomerization of the fifth transmembrane domain from the adenosine A2A receptor. Protein Sci 2005;14:2177–86.CrossRefGoogle Scholar
  221. 221.
    Bouvier M. Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci 2001;2:274–86.PubMedCrossRefGoogle Scholar
  222. 222.
    Whorton MR, Jastrzebska B, Park PSH, et al. Efficient coupling of transducin to monomeric rhodopsin in a phospholipid bilayer. J Biol Chem 2007;282:9297–9301.CrossRefGoogle Scholar
  223. 223.
    Ridge KD, Marino JP, Ngo T, Ramon E, Brabazon DM, Abdulaev NG. NMR analysis of rhodopsin-transducin interactions. Vision Res 2006;46:4482–92.PubMedCrossRefGoogle Scholar
  224. 224.
    Ridge KD, Palczewski K. Visual rhodopsin sees the light: Structure and mechanism of G protein signaling. J Biol Chem 2007;282:9297–9301.PubMedCrossRefGoogle Scholar
  225. 225.
    Brock C, Oueslati N, Soler S, Boudier L, Rondard P, Pin JP. Activation of a dimeric metabotropic glutamate receptor by intersubunit rearrangement. J Biol Chem 2007;282:33000–8.PubMedCrossRefGoogle Scholar
  226. 226.
    Tateyama M, Abe H, Nakata H, Saito O, Kubo Y. Ligand-induced rearrangement of the dimeric metabotropic glutamate receptor 1[alpha]. Nat Struct Mol Biol 2004;11:637–42.PubMedCrossRefGoogle Scholar
  227. 227.
    Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 1996;274:768–70.PubMedCrossRefGoogle Scholar
  228. 228.
    Niv MY, Filizola M. Influence of oligomerization on the dynamics of G-protein coupled receptors as assessed by normal mode analysis. Proteins 2008;71:575–86.PubMedCrossRefGoogle Scholar
  229. 229.
    Goudet C, Kniazeff J, Hlavackova V, et al. Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators. J Biol Chem 2005;280:24380–5.PubMedCrossRefGoogle Scholar
  230. 230.
    Damian M, Mary S, Martin A, Pin JP, Baneres JL. G protein activation by the leukotriene B-4 receptor dimer – Evidence for an absence of trans-activation. J Biol Chem 2008;283: 21084–92.PubMedCrossRefGoogle Scholar
  231. 231.
    Kniazeff J, Galvez T, Labesse G, Pin JP. No ligand binding in the GB2 subunit of the GABAB receptor is required for activation and allosteric interaction between the subunits. J Neurosci 2002;22:7352–61.PubMedGoogle Scholar
  232. 232.
    Xu H, Staszewski L, Tang H, Adler E, Zoller M, Li X. Different functional roles of T1R subunits in the heteromeric taste receptors. Proc Natl Acad Sci USA 2004;101:6.Google Scholar
  233. 233.
    Filipek S, Krzysko KA, Fotiadis D, et al. A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface. Photochem Photobiol Sci 2004;3:628–38.PubMedCrossRefGoogle Scholar
  234. 234.
    Filipek S, Stenkamp RE, Teller DC, Palczewski K. G protein-coupled receptor rhodopsin: a prospectus. Ann Rev Physiol 2003;65:851–79.CrossRefGoogle Scholar
  235. 235.
    Jastrzebska B, Fotiadis D, Jang GF, Stenkamp RE, Engel A, Palczewski K. Functional and structural characterization of rhodopsin oligomers. J Biol Chem 2006;281:11917–22.PubMedCrossRefGoogle Scholar
  236. 236.
    Hamm HE. How activated receptors couple to G proteins. Proc Natl Acad Sci U S A 2001;98:4819–21.PubMedCrossRefGoogle Scholar
  237. 237.
    Lambright DG, Sondek J, Bohm A, Skiba NP, Hamm HE, Sigler PB. The 2.0 A crystal structure of a heterotrimeric G protein. Nature 1996;379:311–9.PubMedCrossRefGoogle Scholar
  238. 238.
    Sondek J, Bohm A, Lambright DG, Hamm HE, Sigler PB. Crystal structure of a G-protein beta gamma dimer at 2.1A resolution. Nature 1996;379:369–74.PubMedCrossRefGoogle Scholar
  239. 239.
    Willardson BM, Pou B, Yoshida T, Bitensky MW. Cooperative binding of the retinal rod G-protein, transducin, to light-activated rhodopsin. J Biol Chem 1993;268:6371–82.PubMedGoogle Scholar
  240. 240.
    Terrillon S, Durroux T, Mouillac B, et al. Oxytocin and vasopressin V1a and V2 receptors form constitutive homo- and heterodimers during biosynthesis. Mol Endocrinol 2003;17:677–91.PubMedCrossRefGoogle Scholar
  241. 241.
    Terrillon S, Bouvier M. Roles of G-protein-coupled receptor dimerization. EMBO Rep 2004;5:30–4.PubMedCrossRefGoogle Scholar
  242. 242.
    Banères J-L, Parello J. Structure-based analysis of GPCR function: Evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G-protein. J Mol Biol 2003;329:815–29.PubMedCrossRefGoogle Scholar
  243. 243.
    Senogles SE, Heimert TL, Odife ER, Quasney MW. A region of the third intracellular loop of the short form of the D2 dopamine receptor dictates Gi coupling specificity. J Biol Chem 2004;279:1601–6.PubMedCrossRefGoogle Scholar
  244. 244.
    Voss T, Wallner E, Czernilofsky AP, Freissmuth M. Amphipathic alpha-helical structure does not predict the ability of receptor-derived synthetic peptides to interact with guanine nucleotide-binding regulatory proteins. J Biol Chem 1993;268:4637–42.PubMedGoogle Scholar
  245. 245.
    Nanoff C, Koppensteiner R, Yang Q, Fuerst E, Ahorn H, Freissmuth M. The carboxyl terminus of the Galpha-subunit is the latch for triggered activation of heterotrimeric G proteins. Mol Pharmacol 2006;69:397–405.PubMedGoogle Scholar
  246. 246.
    Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A 2007;104:2001–6.PubMedCrossRefGoogle Scholar
  247. 247.
    Franco R, Casado V, Cortes A, et al. Basic concepts in G-protein-coupled receptor homo- and heterodimerization. Sci World J 2007;7:48–57.CrossRefGoogle Scholar
  248. 248.
    Franco R, Ciruela F, Casado V, et al. Partners for adenosine A1 receptors. J Mol Neurosci: MN 2005;26:221–32.PubMedCrossRefGoogle Scholar
  249. 249.
    Springael JY, de Poorter C, Deupi X, Van Durme J, Pardo L, Parmentier M. The activation mechanism of chemokine receptor CCR5 involves common structural changes but a different network of interhelical interactions relative to rhodopsin. Cell Signal 2007;19:1446–56.PubMedCrossRefGoogle Scholar
  250. 250.
    Kenakin T. Efficacy at G-protein-coupled receptors. Nat Rev Drug Discov 2002;1:103–10.PubMedCrossRefGoogle Scholar
  251. 251.
    Milligan G, Smith NJ. Allosteric modulation of heterodimeric G-protein-coupled receptors. Trends Pharmacol Sci 2007;28:615–20.PubMedCrossRefGoogle Scholar
  252. 252.
    Jacoby E, Bouhelal R, Gerspacher M, Seuwen K. The 7Â TM G-protein-coupled receptor target family. Chem Med Chem 2006;1:760–82.Google Scholar
  253. 253.
    Pidasheva S, Grant M, Canaff L, Ercan O, Kumar U, Hendy GN. Calcium-sensing receptor dimerizes in the endoplasmic reticulum: biochemical and biophysical characterization of CASR mutants retained intracellularly. Human Mol Gen 2006;15:2200–9.CrossRefGoogle Scholar
  254. 254.
    Calebiro D, de Filippis T, Lucchi S, et al. Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance. Human Mol Gen 2005;14:2991–3002.CrossRefGoogle Scholar
  255. 255.
    McElvaine AT, Mayo KE. A dominant-negative human growth hormone-releasing hormone (GHRH) receptor splice variant inhibits GHRH binding. Endocrinology 2006;147:1884–94.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Irina S. Moreira
    • 1
  • Lei Shi
    • 2
  • Zachary Freyberg
    • 3
  • Spencer S. Ericksen
    • 1
  • Harel Weinstein
    • 4
  • Jonathan A. Javitch
    • 5
  1. 1.Department of Physiology and BiophysicsWeill Medical College of Cornell UniversityNew YorkUSA
  2. 2.Department of Physiology and Biophysics and Institute for Computational BiomedicineWeill Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of PsychiatryColumbia University College of Physicians and SurgeonsNew YorkUSA
  4. 4.Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational BiomedicineWeill Medical College of Cornell UniversityNew YorkUSA
  5. 5.Center for Molecular RecognitionColumbia University College of Physicians and SurgeonsNew YorkUSA

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