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Molecular Mechanisms Involved in the Activation of Rhodopsin-Like Seven-Transmembrane Receptors

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The G Protein-Coupled Receptors Handbook

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

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Abstract

Seven-transmembrane receptors (7TMRs) comprise a large family of membrane-bound proteins that share a unifying signal transduction mechanism (i.e., upon activation, these receptors signal through G proteins). These receptors are involved in a vast variety of physiological functions, including neurotransmission, function of exocrine and endocrine glands, smell, taste, vision, chemotaxis, embryogenesis, development, human immunodeficiency virus (HIV) infection, oncogenesis, cell growth, and differentiation. More recent studies indicate that these receptors are also associated with and signal through other molecules (1). Therefore, it is more appropriate to use the term 7TMR than G protein-coupled receptors (GPCRs).

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References

  1. Hall RA, Premont RT, Lefkowitz RJ. Heptahelical receptor signaling: beyond the G protein paradigm. J Cell Biol 1999;145:927–932.

    Article  PubMed  CAS  Google Scholar 

  2. Schertler GF, Villa C, Henderson R. Projection structure of rhodopsin. Nature 1993;362:770–772.

    Article  PubMed  CAS  Google Scholar 

  3. Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 2000;289:739–745.

    Article  PubMed  CAS  Google Scholar 

  4. Teller DC, Okada T, Behnke CA, Palczewski K, Stenkamp RE. Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). Biochem 2001;40: 7761–7772.

    Article  CAS  Google Scholar 

  5. Visiers I, Ballesteros JA, Weinstein H. Three-dimensional representations of G protein-coupled receptor structures and mechanisms. Methods Enzymol 2002;343:329–371.

    Article  PubMed  Google Scholar 

  6. 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;60:1–19.

    PubMed  CAS  Google Scholar 

  7. Bockaert J, Pin JP. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 1999;18:1723–1729.

    Article  PubMed  CAS  Google Scholar 

  8. Schwartz TW, Holst B. Molecular Structure of G Protein-Coupled Receptors. In: Foreman JC, Johansen T, eds. Textbook of Receptor Pharmacology. New York: CRC Press, 2002, pp. 81–110.

    Google Scholar 

  9. 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.

    CAS  Google Scholar 

  10. Mirzadegan T, Benko G, Filipek S, Palczewski K. Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. Biochem 2003;42:2759–2767.

    Article  CAS  Google Scholar 

  11. Meng EC, Bourne HR. Receptor activation: what does the rhodopsin structure tell us? Trends Pharmacol Sci 2001;22:587–593.

    Article  PubMed  CAS  Google Scholar 

  12. Filipek S, Stenkamp RE, Teller DC, Palczewski K. G protein-coupled receptor rhodopsin: a prospectus. Annu Rev Physiol 2003;65:851–879.

    Article  PubMed  CAS  Google Scholar 

  13. Sakmar TP, Menon ST, Marin EP, Awad ES. Rhodopsin: insights from recent structural studies. Annu Rev Biophys Biomol Struct 2002;31:443–484.

    Article  PubMed  CAS  Google Scholar 

  14. Schertler GF, Hargrave PA. Projection structure of frog rhodopsin in two crystal forms. Proc Natl Acad Sci USA 1995;92:11,578–11,582.

    Article  PubMed  CAS  Google Scholar 

  15. Unger VM, Hargrave PA, Baldwin JM, Schertler GF. Arrangement of rhodopsin transmembrane alpha-helices. Nature 1997;389:203–206.

    Article  PubMed  CAS  Google Scholar 

  16. Borhan B, Souto ML, Imai H, Shichida Y, Nakanishi K. Movement of retinal along the visual transduction path. Science 2000;288:2209–2212.

    Article  PubMed  CAS  Google Scholar 

  17. Filipek S, Teller DC, Palczewski K, Stenkamp R. The crystallographic model of rhodopsin and its use in studies of other G protein-coupled receptors. Annu Rev Biophys Biomol Struct 2003;32:375–397.

    Article  PubMed  CAS  Google Scholar 

  18. Gether U, Kobilka BK. G protein-coupled receptors. II. Mechanism of agonist activation. J Biol Chem 1998;273:17,979–17,982.

    Article  PubMed  CAS  Google Scholar 

  19. Gether U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev 2000;21:90–113.

    Article  PubMed  CAS  Google Scholar 

  20. 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;274:768–770.

    Article  PubMed  CAS  Google Scholar 

  21. Cai K, Klein-Seetharaman J, Hwa J, Hubbell WL, Khorana HG. Structure and function in rhodopsin: effects of disulfide cross-links in the cytoplasmic face of rhodopsin on transducin activation and phosphorylation by rhodopsin kinase. Biochemistry 1999;38:12,893–12,898.

    Article  PubMed  CAS  Google Scholar 

  22. Sheikh SP, Zvyaga TA, Lichtarge O, Sakmar TP, Bourne HR. Rhodopsin activation blocked by metal-ion-binding sites linking transmembrane helices C and F. Nature 1996;383:347–350.

    Article  PubMed  CAS  Google Scholar 

  23. 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. J Biol Chem 1999;274:17,033–17,041.

    Article  PubMed  CAS  Google Scholar 

  24. Hubbell WL, Cafiso DS, Altenbach C. Identifying conformational changes with site-directed spin labeling. Nat Struct Biol 2000;7:735–739.

    Article  PubMed  CAS  Google Scholar 

  25. Altenbach C, Yang K, Farrens DL, Farahbakhsh ZT, Khorana HG, Hubbell WL. Structural features and light-dependent changes in the cytoplasmic interhelical E-F loop region of rhodopsin: a site-directed spin-labeling study. Biochemistry 1996;35:12,470–12,478.

    Article  PubMed  CAS  Google Scholar 

  26. Farahbakhsh ZT, Ridge KD, Khorana HG, Hubbell WL. Mapping light-dependent structural changes in the cytoplasmic loop connecting helices C and D in rhodopsin: a site-directed spin labeling study. Biochemistry 1995;34: 8812–8819.

    Article  PubMed  CAS  Google Scholar 

  27. Gether U, Lin S, Ghanouni P, Ballesteros JA, Weinstein H, Kobilka BK. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. EMBO J 1997;16:6737–6747.

    Article  PubMed  CAS  Google Scholar 

  28. Gether U, Lin S, Kobilka BK. Fluorescent labeling of purified beta 2 adrenergic receptor. Evidence for ligand-specific conformational changes. J Biol Chem 1995;270:28,268–28,275.

    Article  PubMed  CAS  Google Scholar 

  29. Kobilka BK, Gether U. Use of fluorescence spectroscopy to study conformational changes in the beta 2-adrenoceptor. Methods Enzymol 2002;343:170–182.

    PubMed  Google Scholar 

  30. Ward SD, Hamdan FF, Bloodworth LM, Wess J. Conformational changes that occur during m3 muscarinic acetylcholine receptor activation probed by the use of an in situ disulfide cross-linking strategy. J Biol Chem 2002; 277:2247–2257.

    Article  PubMed  CAS  Google Scholar 

  31. Pauwels PJ, Wurch T. Review: amino acid domains involved in constitutive activation of G-protein-coupled receptors. Mol Neurobiol 1998;17:109–135.

    Article  PubMed  CAS  Google Scholar 

  32. 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;13:336–343.

    Article  PubMed  CAS  Google Scholar 

  33. De Lean A, Stadel JM, Lefkowitz RJ. A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem 1980;255:7108–7117.

    PubMed  Google Scholar 

  34. Samama P, Cotecchia S, Costa T, Lefkowitz RJ. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem 1993;268:4625–4636.

    PubMed  CAS  Google Scholar 

  35. Fahmy K, Sakmar TP, Siebert F. Structural determinants of active state conformation of rhodopsin: molecular biophysics approaches. Methods Enzymol 2000;315:178–196.

    PubMed  CAS  Google Scholar 

  36. Kjelsberg MA, Cotecchia S, Ostrowski J, Caron MG, Lefkowitz RJ. Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation. J Biol Chem 1992;267:1430–1433.

    PubMed  CAS  Google Scholar 

  37. Befort K, Zilliox C, Filliol D, Yue S, Kieffer BL. Constitutive activation of the delta opioid receptor by mutations in transmembrane domains III and VII. J Biol Chem 1999;274:18,574–18,581 [published erratum appears in J Biol Chem 1999;274(39):28,058].

    Article  PubMed  CAS  Google Scholar 

  38. Gether U, Ballesteros JA, Seifert R, Sanders-Bush 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;272:2587–2590.

    Article  PubMed  CAS  Google Scholar 

  39. Rasmussen SG, Jensen AD, Liapakis G, Ghanouni P, Javitch JA, Gether U. Mutation of a highly conserved aspartic acid in the beta2 adrenergic receptor: constitutive activation, structural instability, and conformational rearrangement of transmembrane segment 6. Mol Pharmacol 1999;56:175–184.

    PubMed  CAS  Google Scholar 

  40. Chen S, Lin F, Xu M, Graham RM. Phe(303) in TMVI of the alpha(1B)-adrenergic receptor is a key residue coupling TM helical movements to G-protein activation. Biochem 2002;41:588–596.

    Article  CAS  Google Scholar 

  41. Alewijnse AE, Timmerman H, Jacobs EH, et al. The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H-2 receptor. Mol Pharmacol 2000;57:890–898.

    PubMed  CAS  Google Scholar 

  42. Li J, Chen C, Huang P, Liu-Chen L-Y. Inverse agonist up-regulates the constitutively active D3.49(164)Q mutant of the rat μ opioid receptor by stabilizing the structure and blocking constitutive internalization and down-regulation. Mol Pharmacol 2001;60:1064–1075.

    PubMed  CAS  Google Scholar 

  43. Li J, Huang P, Chen C, de Riel JK, Weinstein H, Liu-Chen L-Y. 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;40:12,039–12,050.

    Article  PubMed  CAS  Google Scholar 

  44. Huang P, Li J, Chen C, Visiers I, Weinstein H, Liu-Chen L-Y. 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. Biochem 2001;40:13,501–13,509.

    Article  CAS  Google Scholar 

  45. Probst WC, Snyder LA, Schuster DI, Brosius J, Sealfon SC. Sequence alignment of the G-protein coupled receptor superfamily. DNA Cell Biol 1992;11:1–20.

    PubMed  CAS  Google Scholar 

  46. 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: 10,445–10,453.

    Article  PubMed  CAS  Google Scholar 

  47. Oliveira L, Paiva AC, Sander C, Vriend G. A common step for signal transduction in G protein-coupled receptors. Trends Pharmacol Sci 1994;15:170–172.

    Article  PubMed  CAS  Google Scholar 

  48. Radding CM, Wald G. The stability of rhodopsin and opsin; effects of pH and aging. J Gen Physiol 1956; 39:923–933.

    Article  PubMed  CAS  Google Scholar 

  49. Radding CM, Wald G. Acid-base properties of rhodopsin and opsin. J Gen Physiol 1956;39:909–922.

    Article  PubMed  CAS  Google Scholar 

  50. Parkes JH, Liebman PA. Temperature and pH dependence of the metarhodopsin I-metarhodopsin II kinetics and equilibria in bovine rod disk membrane suspensions. Biochem 1984;23:5054–5061.

    Article  CAS  Google Scholar 

  51. Arnis S, Fahmy K, Hofmann KP, Sakmar TP. A conserved carboxylic acid group mediates light-dependent proton uptake and signaling by rhodopsin. J Biol Chem 1994;269:23,879–23,881.

    PubMed  CAS  Google Scholar 

  52. Fahmy K, Jager F, Beck M, Zvyaga TA, Sakmar TP, Siebert F. Protonation states of membrane-embedded carboxylic acid groups in rhodopsin and metarhodopsin II: a Fourier-transform infrared spectroscopy study of site-directed mutants. Proc Natl Acad Sci USA 1993;90:10,206–10,210.

    Article  PubMed  CAS  Google Scholar 

  53. Ghanouni P, Schambye H, Seifert R, et al. The effect of pH on beta(2) adrenoceptor function. Evidence for protonation-dependent activation. J Biol Chem 2000;275:3121–3127.

    Article  PubMed  CAS  Google Scholar 

  54. Scheer A, Fanelli F, Costa T, De Benedetti PG, Cotecchia S. The activation process of the alpha1B-adrenergic receptor: potential role of protonation and hydrophobicity of a highly conserved aspartate. Proc Natl Acad Sci USA 1997;94:808–813.

    Article  PubMed  CAS  Google Scholar 

  55. Gether U, Asmar F, Meinild AK, Rasmussen SG. Structural basis for activation of G-protein-coupled receptors. Pharmacol Toxicol 2002;91:304–312.

    Article  PubMed  CAS  Google Scholar 

  56. Cohen GB, Yang T, Robinson PR, Oprian DD. Constitutive activation of opsin: influence of charge at position 134 and size at position 296. Biochem 1993;32:6111–6115.

    Article  CAS  Google Scholar 

  57. Kim JM, Altenbach C, Thurmond RL, Khorana HG, Hubbell WL. Structure and function in rhodopsin: rhodopsin mutants with a neutral amino acid at E134 have a partially activated conformation in the dark state. Proc Natl Acad Sci USA 1997;94:14,273–14,278.

    Article  PubMed  CAS  Google Scholar 

  58. Scheer A, Fanelli F, Costa T, De Benedetti PG, Cotecchia S. Constitutively active mutants of the alpha 1B-adrenergic receptor: role of highly conserved polar amino acids in receptor activation. EMBO J 1996;15: 3566–3578.

    PubMed  CAS  Google Scholar 

  59. Morin D, Cotte N, Balestre MN, et al. The D136A mutation of the V2 vasopressin receptor induces a constitutive activity which permits discrimination between antagonists with partial agonist and inverse agonist activities. FEBS Lett 1998;441:470–475.

    Article  PubMed  CAS  Google Scholar 

  60. Burger M, Burger JA, Hoch RC, Oades Z, Takamori H, Schraufstatter IU. Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi’s sarcoma herpesvirus-G protein-coupled receptor. J Immunol 1999;163:2017–2022.

    PubMed  CAS  Google Scholar 

  61. Ho HH, Du D, Gershengorn MC. The N terminus of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor is necessary for high affinity chemokine binding but not for constitutive activity. J Biol Chem 1999; 274:31,327–31,332.

    Article  PubMed  CAS  Google Scholar 

  62. Ho HH, Ganeshalingam N, Rosenhouse-Dantsker A, Osman R, Gershengorn MC. Charged residues at the intracellular boundary of transmembrane helices 2 and 3 independently affect constitutive activity of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. J Biol Chem 2001;276:1376–1382.

    Article  PubMed  CAS  Google Scholar 

  63. 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: 29,171–29,177.

    Article  PubMed  CAS  Google Scholar 

  64. Lu ZL, Curtis CA, Jones PG, Pavia J, Hulme EC. The role of the aspartate-arginine-tyrosine triad in the m1 muscarinic receptor: mutations of aspartate 122 and tyrosine 124 decrease receptor expression but do not abolish signaling. Mol Pharmacol 1997;51:234–241.

    PubMed  CAS  Google Scholar 

  65. Wang Z, Wang H, Ascoli M. Mutation of a highly conserved acidic residue present in the second intracellular loop of G-protein-coupled receptors does not impair hormone binding or signal transduction of the luteinizing hormone/chorionic gonadotropin receptor. Mol Endocrinol 1993;7:85–93.

    Article  PubMed  CAS  Google Scholar 

  66. Arora KK, Cheng Z, Catt KJ. Mutations of the conserved DRS motif in the second intracellular loop of the gonadotropin-releasing hormone receptor affect expression, activation, and internalization. Mol Endocrinol 1997; 11:1203–1212.

    Article  PubMed  CAS  Google Scholar 

  67. Ren Q., Kurose H, Lefkowitz RJ, Cotecchia S. Constitutively active mutants of the alpha 2-adrenergic receptor. J Biol Chem 1993;268:16,483–16,487 [published erratum appears in J Biol Chem 1994;269(2):1566].

    PubMed  CAS  Google Scholar 

  68. Lattion A, Abuin L, Nenniger-Tosato M, Cotecchia S. Constitutively active mutants of the beta1-adrenergic receptor. FEBS Lett 1999;457:302–306.

    Article  PubMed  CAS  Google Scholar 

  69. Egan CT, Herrick-Davis K, Teitler M. Creation of a constitutively activated state of the 5-hydroxytryptamine2A receptor by site-directed mutagenesis: inverse agonist activity of antipsychotic drugs. J Pharmacol Exp Ther 1998; 286:85–90.

    PubMed  CAS  Google Scholar 

  70. Herrick-Davis K, Egan C, Teitler M. Activating mutations of the serotonin 5-HT2C receptor. J Neurochem 1997;69:1138–1144.

    PubMed  CAS  Google Scholar 

  71. Pauwels PJ, Gouble A, Wurch T. Activation of constitutive 5-hydroxytryptamine(1B) receptor by a series of mutations in the BBXXB motif: positioning of the third intracellular loop distal junction and its G(o)alpha protein interactions. Biochem J 1999;343(pt 2):435–442.

    Article  PubMed  CAS  Google Scholar 

  72. Hogger P, Shockley MS, Lameh J, Sadee W. Activating and inactivating mutations in N-and C-terminal i3 loop junctions of muscarinic acetylcholine Hm1 receptors. J Biol Chem 1995;270:7405–7410.

    Article  PubMed  CAS  Google Scholar 

  73. Visiers I, Ebersole BJ, Dracheva S, Ballesteros JA, Sealfon SC, Weinstein H. Structural motifs as functional microdomains in G protein-coupled receptors: energetic considerations in the mechanism of activation of the serotonin 5HT2A receptor by disruption of the ionic lock of the arginine cage. Int J Quant Chem 2002;88:65–75.

    Article  CAS  Google Scholar 

  74. 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;277:11,441–11,449.

    Article  PubMed  CAS  Google Scholar 

  75. Greasley PJ, Fanelli F, Rossier O, Abuin L, Cotecchia S. Mutagenesis and modelling of the alpha(1b)-adrenergic receptor highlight the role of the helix 3/helix 6 interface in receptor activation. Mol Pharmacol 2002;61: 1025–1032.

    Article  PubMed  CAS  Google Scholar 

  76. Laue L, Chan WY, Hsueh AJ, et al. Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty. Proc Natl Acad Sci USA 1995;92: 1906–1910.

    Article  PubMed  CAS  Google Scholar 

  77. Kosugi S, Mori T, Shenker A. An anionic residue at position 564 is important for maintaining the inactive conformation of the human lutropin/choriogonadotropin receptor. Mol Pharmacol 1998;53:894–901.

    PubMed  CAS  Google Scholar 

  78. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas [see comments]. Nature 1993;365:649–651.

    Article  PubMed  CAS  Google Scholar 

  79. Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 2002;23:141–174.

    Article  PubMed  CAS  Google Scholar 

  80. Schulz A, Schoneberg T, Paschke R, Schultz G, Gudermann T. Role of the third intracellular loop for the activation of gonadotropin receptors. Mol Endocrinol 1999;13:181–190.

    Article  PubMed  CAS  Google Scholar 

  81. 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;41:11,972–11,980.

    Article  PubMed  CAS  Google Scholar 

  82. Franke RR, Sakmar TP, Graham RM, Khorana HG. Structure and function in rhodopsin. Studies of the interaction between the rhodopsin cytoplasmic domain and transducin. J Biol Chem 1992;267:14,767–14,774.

    PubMed  CAS  Google Scholar 

  83. Rosenthal W, Antaramian A, Gilbert S, Birnbaumer M. Nephrogenic diabetes insipidus. A V2 vasopressin receptor unable to stimulate adenylyl cyclase. J Biol Chem 1993;268:13,030–13,033.

    PubMed  CAS  Google Scholar 

  84. Jones PG, Curtis CA, Hulme EC. The function of a highly-conserved arginine residue in activation of the muscarinic m1 receptor. Eur J Pharmacol 1995;288:251–257.

    Article  PubMed  CAS  Google Scholar 

  85. Rhee MH, Nevo I, Levy R, Vogel Z. Role of the highly conserved Asp-Arg-Tyr motif in signal transduction of the CB2 cannabinoid receptor. FEBS Lett 2000;466:300–304.

    Article  PubMed  CAS  Google Scholar 

  86. Scheer A, Costa T, Fanelli F, et al. Mutational analysis of the highly conserved arginine within the Glu/Asp-Arg-Tyr motif of the alpha(1b)-adrenergic receptor: effects on receptor isomerization and activation. Mol Pharmacol 2000;57:219–231.

    PubMed  CAS  Google Scholar 

  87. Acharya S, Karnik SS. Modulation of GDP release from transducin by the conserved Glu134-Arg135 sequence in rhodopsin. J Biol Chem 1996;271:25,406–25,411.

    Article  PubMed  CAS  Google Scholar 

  88. Fanelli F, Barbier P, Zanchetta D, De Benedetti PG, Chini B. Activation mechanism of human oxytocin receptor: a combined study of experimental and computer-simulated mutagenesis. Mol Pharmacol 1999;56: 214–225.

    PubMed  CAS  Google Scholar 

  89. Chen S, Xu M, Lin F, Lee D, Riek P, Graham RM. Phe310 in transmembrane VI of the alpha1B-adrenergic receptor is a key switch residue involved in activation and catecholamine ring aromatic bonding. J Biol Chem 1999; 274: 16,320–16,330.

    Article  PubMed  CAS  Google Scholar 

  90. Chen S, Lin F, Xu M, Riek RP, Novotny J, Graham RM. Mutation of a single TMVI residue, Phe(282), in the beta(2)-adrenergic receptor results in structurally distinct activated receptor conformations. Biochemistry 2002; 41: 6045–6053.

    Article  PubMed  CAS  Google Scholar 

  91. 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: 40,989–40,996.

    Article  PubMed  CAS  Google Scholar 

  92. Marie J, Richard E, Pruneau D, et al. Control of conformational equilibria in the human B2 bradykinin receptor. Modeling of nonpeptidic ligand action and comparison to the rhodopsin structure. J Biol Chem 2001;276: 41,100–41,111.

    Article  PubMed  CAS  Google Scholar 

  93. Shinozaki H, Fanelli F, Liu X, Jaquette J, Nakamura K, Segaloff DL. Pleiotropic effects of substitutions of a highly conserved leucine in transmembrane helix III of the human lutropin/choriogonadotropin receptor with respect to constitutive activation and hormone responsiveness. Mol Endocrinol 2001;15:972–984.

    Article  PubMed  CAS  Google Scholar 

  94. Fritze O, Filipek S, Kuksa V, Palczewski K, Hofmann KP, Ernst OP. Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activation. Proc Natl Acad Sci USA 2003;100:2290–2295.

    Article  PubMed  CAS  Google Scholar 

  95. 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;277:36,577–36,584.

    Article  PubMed  CAS  Google Scholar 

  96. Porter JE, Hwa J, Perez DM. Activation of the alpha1b-adrenergic receptor is initiated by disruption of an interhelical salt bridge constraint. J Biol Chem 1996;271:28,318–28,323.

    Article  PubMed  CAS  Google Scholar 

  97. Robinson PR, Cohen GB, Zhukovsky EA, Oprian DD. Constitutively active mutants of rhodopsin. Neuron 1992;9:719–725.

    Article  PubMed  CAS  Google Scholar 

  98. Kristiansen K, Kroeze WK, Willins DL, et al. A highly conserved aspartic acid (Asp-155) anchors the terminal amine moiety of tryptamines and is involved in membrane targeting of the 5-HT(2A) serotonin receptor but does not participate in activation via a “salt-bridge disruption” mechanism. J Pharmacol Exp Ther 2000; 293:735–746.

    PubMed  CAS  Google Scholar 

  99. Gerber BO, Meng EC, Dotsch V, Baranski TJ, Bourne HR. An activation switch in the ligand binding pocket of the C5a receptor. J Biol Chem 2001;276:3394–3400.

    Article  PubMed  CAS  Google Scholar 

  100. Govaerts C, Lefort A, Costagliola S, et al. A conserved Asn in transmembrane helix 7 is an on/off switch in the activation of the thyrotropin receptor. J Biol Chem 2001;276:22,991–22,999.

    Article  PubMed  CAS  Google Scholar 

  101. Xu W, Ozdener F, Li J-G, et al. Functional role of the spatial proximity of Asp114(2.50) in TMH 2 and Asn332(7.49) in TMH 7 of the mu opioid receptor. FEBS Lett 1999;447:318–324.

    Article  PubMed  CAS  Google Scholar 

  102. Altenbach C, Cai K, Klein-Seetharaman J, Khorana HG, Hubbell WL. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 65 in helix TM1 and residues in the sequence 306–319 at the cytoplasmic end of helix TM7 and in helix H8. Biochemistry 2001;40:15,483–15,492.

    Article  PubMed  CAS  Google Scholar 

  103. Altenbach C, Oh KJ, Trabanino RJ, Hideg K, Hubbell WL. Estimation of inter-residue distances in spin labeled proteins at physiological temperatures: experimental strategies and practical limitations. Biochem 2001;40: 15,471–15,482.

    Article  CAS  Google Scholar 

  104. Elling CE, Thirstrup K, Holst B, Schwartz TW. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor. Proc Natl Acad Sci USA 1999;96:12,322–12,327.

    Article  PubMed  CAS  Google Scholar 

  105. Holst B, Elling CE, Schwartz TW. Partial agonism through a zinc-Ion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor. Mol Pharmacol 2000;58:263–270.

    PubMed  CAS  Google Scholar 

  106. Roberts DD, Lewis SD, Ballou DP, Olson ST, Shafer JA. Reactivity of small thiolate anions and cysteine-25 in papain toward methyl methanethiosulfonate. Biochemistry 1986;25:5595–5601.

    Article  PubMed  CAS  Google Scholar 

  107. Karlin A, Akabas MH. Substituted-cysteine accessibility method. Methods Enzymol 1998;293: 123–145.

    PubMed  CAS  Google Scholar 

  108. Javitch JA, Fu D, Liapakis G, Chen J. Constitutive activation of the beta2 adrenergic receptor alters the orientation of its sixth membrane-spanning segment. J Biol Chem 1997;272:18,546–18,549.

    Article  PubMed  CAS  Google Scholar 

  109. Perez DM, Hwa J, Gaivin R, Mathur M, Brown F, Graham RM. Constitutive activation of a single effector pathway: evidence for multiple activation states of a G protein-coupled receptor. Mol Pharmacol 1996;49: 112–122.

    PubMed  CAS  Google Scholar 

  110. Zuscik MJ, Porter JE, Gaivin R, Perez DM. Identification of a conserved switch residue responsible for selective constitutive activation of the beta2-adrenergic receptor. J Biol Chem 1998;273:3401–3407.

    Article  PubMed  CAS  Google Scholar 

  111. Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 2001;53:1–24.

    PubMed  CAS  Google Scholar 

  112. Pei G, Samama P, Lohse M, et al. A constitutively active mutant beta 2-adrenergic receptor is constitutively desensitized and phosphorylated. Proc Natl Acad Sci USA 1994;91:2699–2702.

    Article  PubMed  CAS  Google Scholar 

  113. Rim J, Oprian DD. Constitutive activation of opsin: interaction of mutants with rhodopsin kinase and arrestin. Biochemistry 1995;34:11,938–11,945.

    Article  PubMed  CAS  Google Scholar 

  114. Thomas WG, Qian H, Chang CS, Karnik S. Agonist-induced phosphorylation of the angiotensin II (AT(1A)) receptor requires generation of a conformation that is distinct from the inositol phosphate-signaling state. J Biol Chem 2000;275:2893–2900.

    Article  PubMed  CAS  Google Scholar 

  115. Mhaouty-Kodja S, Barak LS, Scheer A, et al. Constitutively active alpha-1b adrenergic receptor mutants display different phosphorylation and internalization features. Mol Pharmacol 1999;55:339–347.

    PubMed  CAS  Google Scholar 

  116. Whistler JL, Gerber BO, Meng EC, Baranski TJ, von Zastrow M, Bourne HR. Constitutive activation and endocytosis of the complement factor 5a receptor: evidence for multiple activated conformations of a G protein-coupled receptor. Traffic 2002;3:866–877.

    Article  PubMed  CAS  Google Scholar 

  117. Arden JR, Segredo V, Wang Z, Lameh J, Sadee W. Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged mu-opioid receptor expressed in HEK 293 cells. J Neurochem 1995;65:1636–1645.

    Article  PubMed  CAS  Google Scholar 

  118. Keith DE, Murray SR, Zaki PA, et al. Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 1996;271:19,021–19,024.

    Article  PubMed  CAS  Google Scholar 

  119. Sternini C, Spann M, Anton B, et al. Agonist-selective endocytosis of mu opioid receptor by neurons in vivo. Proc Natl Acad Sci USA 1996;93:9241–9246.

    Article  PubMed  CAS  Google Scholar 

  120. Zhang J, Ferguson SS, Barak LS, et al. Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness. Proc Natl Acad Sci USA 1998;95:7157–7162.

    Article  PubMed  CAS  Google Scholar 

  121. Li JG, Zhang F, Jin XL, Liu-Chen LY. Differential regulation of the human kappa opioid receptor by agonists: etorphine and levorphanol reduced dynorphin A-and U50,488H-induced internalization and phosphorylation. J Pharmacol Exp Ther 2003;305:531–540.

    Article  PubMed  CAS  Google Scholar 

  122. Parnot C, Bardin S, Miserey-Lenkei S, Guedin D, Corvol P, Clauser E. 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;97:7615–7620.

    Article  PubMed  CAS  Google Scholar 

  123. Schmidt C, Li B, Bloodworth L, Erlenbach I, Zeng FY, Wess J. Random mutagenesis of the m3 muscarinic acetylcholine receptor expressed in yeast. Identification of point mutations that “silence” a constitutively active mutant M3 receptor and greatly impair receptor/G protein coupling. J Biol Chem 2003; 278: 30,248–30,260.

    Article  PubMed  CAS  Google Scholar 

  124. Spalding TA, Burstein ES. Constitutively active muscarinic receptors. Life Sci 2001;68: 2511–2516.

    Article  PubMed  CAS  Google Scholar 

  125. Baranski TJ, Herzmark P, Lichtarge O, et al. C5a receptor activation. Genetic identification of critical residues in four transmembrane helices. J Biol Chem 1999;274:15,757–15,765.

    Article  PubMed  CAS  Google Scholar 

  126. Decaillot FM, Befort K, Filliol D, Yue S, Walker P, Kieffer BL. Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation. Nat Struct Biol 2003;10:629–636.

    Article  PubMed  CAS  Google Scholar 

  127. Brillet K, Kieffer BL, Massotte D. Enhanced spontaneous activity of the mu opioid receptor by cysteine mutations: characterization of a tool for inverse agonist screening. BMC Pharmacol 2003;3:14.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA

    Peng Huang PhD & Lee-Yuan Liu-Chen PhD

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  1. Peng Huang PhD
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  2. Lee-Yuan Liu-Chen PhD
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Editors and Affiliations

  1. Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY

    Lakshmi A. Devi PhD

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© 2005 Humana Press Inc., Totowa, NJ

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Huang, P., Liu-Chen, LY. (2005). Molecular Mechanisms Involved in the Activation of Rhodopsin-Like Seven-Transmembrane Receptors. In: Devi, L.A. (eds) The G Protein-Coupled Receptors Handbook. Contemporary Clinical Neuroscience. Humana Press. https://doi.org/10.1007/978-1-59259-919-6_2

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