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The G Protein-Coupled Receptor Rhodopsin: A Historical Perspective

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Rhodopsin

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1271))

Abstract

Rhodopsin is a key light-sensitive protein expressed exclusively in rod photoreceptor cells of the retina. Failure to express this transmembrane protein causes a lack of rod outer segment formation and progressive retinal degeneration, including the loss of cone photoreceptor cells. Molecular studies of rhodopsin have paved the way to understanding a large family of cell-surface membrane proteins called G protein-coupled receptors (GPCRs). Work started on rhodopsin over 100 years ago still continues today with substantial progress made every year. These activities underscore the importance of rhodopsin as a prototypical GPCR and receptor required for visual perception—the fundamental process of translating light energy into a biochemical cascade of events culminating in vision.

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References

  1. Kuhne W (1977) Chemical processes in the retina. Vision Res 17:1269–1316

    Article  CAS  PubMed  Google Scholar 

  2. Salom D, Le Trong I, Pohl E et al (2006) Improvements in G protein-coupled receptor purification yield light stable rhodopsin crystals. J Struct Biol 156:497–504

    Article  CAS  PubMed  Google Scholar 

  3. Salom D, Lodowski DT, Stenkamp RE et al (2006) Crystal structure of a photoactivated deprotonated intermediate of rhodopsin. Proc Natl Acad Sci U S A 103:16123–16128

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kiser PD, Golczak M, Palczewski K (2014) Chemistry of the retinoid (visual) cycle. Chem Rev 114:194–232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Wald G (1968) Molecular basis of visual excitation. Science 162:230–239

    Article  CAS  PubMed  Google Scholar 

  6. Wald G (1935) Carotenoids and the visual cycle. J Gen Physiol 19:351–371

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Hubbard R, Wald G (1952) Cis-trans isomers of vitamin A and retinene in the rhodopsin system. J Gen Physiol 36:269–315

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Wald G, Brown PK (1953) The molar extinction of rhodopsin. J Gen Physiol 37:189–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Matthews RG, Hubbard R, Brown PK et al (1963) Tautomeric forms of metarhodopsin. J Gen Physiol 47:215–240

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Zhukovsky EA, Robinson PR, Oprian DD (1992) Changing the location of the Schiff base counterion in rhodopsin. Biochemistry 31:10400–10405

    Article  CAS  PubMed  Google Scholar 

  11. Zvyaga TA, Min KC, Beck M et al (1993) Movement of the retinylidene Schiff base counterion in rhodopsin by one helix turn reverses the pH dependence of the metarhodopsin I to metarhodopsin II transition. J Biol Chem 268:4661–4667

    CAS  PubMed  Google Scholar 

  12. Palczewski K (2006) G protein-coupled receptor rhodopsin. Annu Rev Biochem 75:743–767

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Palczewski K (2012) Chemistry and biology of vision. J Biol Chem 287:1612–1619

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Mustafi D, Maeda T, Kohno H et al (2012) Inflammatory priming predisposes mice to age-related retinal degeneration. J Clin Invest 122:2989–3001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Jeon CJ, Strettoi E, Masland RH (1998) The major cell populations of the mouse retina. J Neurosci 18:8936–8946

    CAS  PubMed  Google Scholar 

  16. Curcio CA, Sloan KR Jr, Packer O et al (1987) Distribution of cones in human and monkey retina: individual variability and radial asymmetry. Science 236:579–582

    Article  CAS  PubMed  Google Scholar 

  17. Nickell S, Park PS, Baumeister W et al (2007) Three-dimensional architecture of murine rod outer segments determined by cryoelectron tomography. J Cell Biol 177:917–925

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Filipek S, Stenkamp RE, Teller DC et al (2003) G protein-coupled receptor rhodopsin: a prospectus. Annu Rev Physiol 65:851–879

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Oprian DD, Molday RS, Kaufman RJ et al (1987) Expression of a synthetic bovine rhodopsin gene in monkey kidney cells. Proc Natl Acad Sci U S A 84:8874–8878

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Hubbell WL, Altenbach C, Hubbell CM et al (2003) Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide cross-linking. Adv Protein Chem 63:243–290

    Article  CAS  PubMed  Google Scholar 

  21. Grunbeck A, Huber T, Abrol R et al (2012) Genetically encoded photo-cross-linkers map the binding site of an allosteric drug on a G protein-coupled receptor. ACS Chem Biol 7:967–972

    Article  CAS  PubMed  Google Scholar 

  22. Daggett KA, Sakmar TP (2011) Site-specific in vitro and in vivo incorporation of molecular probes to study G-protein-coupled receptors. Curr Opin Chem Biol 15:392–398

    Article  CAS  PubMed  Google Scholar 

  23. Salom D, Cao P, Sun W et al (2012) Heterologous expression of functional G-protein-coupled receptors in Caenorhabditis elegans. FASEB J 26:492–502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Cao P, Sun W, Kramp K et al (2012) Light-sensitive coupling of rhodopsin and melanopsin to G(i/o) and G(q) signal transduction in Caenorhabditis elegans. FASEB J 26:480–491

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Teller DC, Okada T, Behnke CA et al (2001) Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). Biochemistry 40:7761–7772

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Menon ST, Han M, Sakmar TP (2001) Rhodopsin: structural basis of molecular physiology. Physiol Rev 81:1659–1688

    CAS  PubMed  Google Scholar 

  28. Smith SO (2010) Structure and activation of the visual pigment rhodopsin. Annu Rev Biophys 39:309–328

    Article  CAS  PubMed  Google Scholar 

  29. Park JH, Morizumi T, Li Y et al (2013) Opsin, a structural model for olfactory receptors? Angew Chem Int Ed Engl 52:11021–11024

    Article  CAS  PubMed  Google Scholar 

  30. Choe HW, Kim YJ, Park JH et al (2011) Crystal structure of metarhodopsin II. Nature 471:651–655

    Article  CAS  PubMed  Google Scholar 

  31. Scheerer P, Park JH, Hildebrand PW et al (2008) Crystal structure of opsin in its G-protein-interacting conformation. Nature 455:497–502

    Article  CAS  PubMed  Google Scholar 

  32. Park JH, Scheerer P, Hofmann KP et al (2008) Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 454:183–187

    Article  CAS  PubMed  Google Scholar 

  33. Park JH, Krauss N, Pulvermuller A et al (2005) Crystallization and preliminary X-ray studies of mouse centrin1. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:510–513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Singhal A, Ostermaier MK, Vishnivetskiy SA et al (2013) Insights into congenital stationary night blindness based on the structure of G90D rhodopsin. EMBO Rep 14:520–526

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Deupi X, Edwards P, Singhal A et al (2012) Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II. Proc Natl Acad Sci U S A 109:119–124

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Standfuss J, Xie G, Edwards PC et al (2007) Crystal structure of a thermally stable rhodopsin mutant. J Mol Biol 372:1179–1188

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Li J, Edwards PC, Burghammer M et al (2004) Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol 343:1409–1438

    Article  CAS  PubMed  Google Scholar 

  38. Nakamichi H, Okada T (2007) X-ray crystallographic analysis of 9-cis-rhodopsin, a model analogue visual pigment. Photochem Photobiol 83:232–235

    Article  CAS  PubMed  Google Scholar 

  39. Schreiber M, Sugihara M, Okada T et al (2006) Quantum mechanical studies on the crystallographic model of bathorhodopsin. Angew Chem Int Ed Engl 45:4274–4277

    Article  CAS  PubMed  Google Scholar 

  40. Nakamichi H, Okada T (2006) Local peptide movement in the photoreaction intermediate of rhodopsin. Proc Natl Acad Sci U S A 103:12729–12734

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Okada T, Sugihara M, Bondar AN et al (2004) The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol 342:571–583

    Article  CAS  PubMed  Google Scholar 

  42. Nakamichi H, Buss V, Okada T (2007) Photoisomerization mechanism of rhodopsin and 9-cis-rhodopsin revealed by x-ray crystallography. Biophys J 92:L106–L108

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Palczewski K, Orban T (2013) From atomic structures to neuronal functions of g protein-coupled receptors. Annu Rev Neurosci 36:139–164

    Article  CAS  PubMed  Google Scholar 

  44. Ovchinnikov YA (1987) Structure of rhodopsin and bacteriorhodopsin. Photochem Photobiol 45:909–914

    Article  CAS  PubMed  Google Scholar 

  45. Hargrave PA (2001) Rhodopsin structure, function, and topography the Friedenwald lecture. Invest Ophthalmol Vis Sci 42:3–9

    CAS  PubMed  Google Scholar 

  46. Mirzadegan T, Benko G, Filipek S et al (2003) Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. Biochemistry 42:2759–2767

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Applebury ML, Hargrave PA (1986) Molecular biology of the visual pigments. Vision Res 26:1881–1895

    Article  CAS  PubMed  Google Scholar 

  48. Karnik SS, Sakmar TP, Chen HB et al (1988) Cysteine residues 110 and 187 are essential for the formation of correct structure in bovine rhodopsin. Proc Natl Acad Sci U S A 85:8459–8463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Karnik SS, Khorana HG (1990) Assembly of functional rhodopsin requires a disulfide bond between cysteine residues 110 and 187. J Biol Chem 265:17520–17524

    CAS  PubMed  Google Scholar 

  50. Papac DI, Thornburg KR, Bullesbach EE et al (1992) Palmitylation of a G-protein coupled receptor. Direct analysis by tandem mass spectrometry. J Biol Chem 267:16889–16894

    CAS  PubMed  Google Scholar 

  51. Ovchinnikov YA, Abdulaev NG, Bogachuk AS (1988) Two adjacent cysteine residues in the C-terminal cytoplasmic fragment of bovine rhodopsin are palmitylated. FEBS Lett 230:1–5

    Article  CAS  PubMed  Google Scholar 

  52. Maeda A, Okano K, Park PS et al (2010) Palmitoylation stabilizes unliganded rod opsin. Proc Natl Acad Sci U S A 107:8428–8433

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Kaushal S, Ridge KD, Khorana HG (1994) Structure and function in rhodopsin: the role of asparagine-linked glycosylation. Proc Natl Acad Sci U S A 91:4024–4028

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Wheatley M, Wootten D, Conner MT et al (2012) Lifting the lid on GPCRs: the role of extracellular loops. Br J Pharmacol 165:1688–1703

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Wheatley M, Hawtin SR (1999) Glycosylation of G-protein-coupled receptors for hormones central to normal reproductive functioning: its occurrence and role. Hum Reprod Update 5:356–364

    Article  CAS  PubMed  Google Scholar 

  56. Kranich H, Bartkowski S, Denton MJ et al (1993) Autosomal dominant ‘sector’ retinitis pigmentosa due to a point mutation predicting an Asn-15-Ser substitution of rhodopsin. Hum Mol Genet 2:813–814

    Article  CAS  PubMed  Google Scholar 

  57. Fukuda MN, Papermaster DS, Hargrave PA (1979) Rhodopsin carbohydrate. Structure of small oligosaccharides attached at two sites near the NH2 terminus. J Biol Chem 254:8201–8207

    CAS  PubMed  Google Scholar 

  58. Salom D, Wang B, Dong Z et al (2012) Post-translational modifications of the serotonin type 4 receptor heterologously expressed in mouse rod cells. Biochemistry 51:214–224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Crouch RK (1986) Studies of rhodopsin and bacteriorhodopsin using modified retinals. Photochem Photobiol 44:803–807

    Article  CAS  PubMed  Google Scholar 

  60. Estevez ME, Kolesnikov AV, Ala-Laurila P et al (2009) The 9-methyl group of retinal is essential for rapid Meta II decay and phototransduction quenching in red cones. J Gen Physiol 134:137–150

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Buczylko J, Saari JC, Crouch RK et al (1996) Mechanisms of opsin activation. J Biol Chem 271:20621–20630

    Article  CAS  PubMed  Google Scholar 

  62. Palczewski K (2010) Retinoids for treatment of retinal diseases. Trends Pharmacol Sci 31:284–295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Maeda T, Imanishi Y, Palczewski K (2003) Rhodopsin phosphorylation: 30 years later. Prog Retin Eye Res 22:417–434

    Article  CAS  PubMed  Google Scholar 

  64. Ohguro H, Palczewski K, Ericsson LH et al (1993) Sequential phosphorylation of rhodopsin at multiple sites. Biochemistry 32:5718–5724

    Article  CAS  PubMed  Google Scholar 

  65. Palczewski K, Buczylko J, Kaplan MW et al (1991) Mechanism of rhodopsin kinase activation. J Biol Chem 266:12949–12955

    CAS  PubMed  Google Scholar 

  66. Kennedy MJ, Lee KA, Niemi GA et al (2001) Multiple phosphorylation of rhodopsin and the in vivo chemistry underlying rod photoreceptor dark adaptation. Neuron 31:87–101

    Article  CAS  PubMed  Google Scholar 

  67. Lee KA, Nawrot M, Garwin GG et al (2010) Relationships among visual cycle retinoids, rhodopsin phosphorylation, and phototransduction in mouse eyes during light and dark adaptation. Biochemistry 49:2454–2463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Struts AV, Salgado GF, Martinez-Mayorga K et al (2011) Retinal dynamics underlie its switch from inverse agonist to agonist during rhodopsin activation. Nat Struct Mol Biol 18:392–394

    Article  CAS  PubMed  Google Scholar 

  69. Renthal R (2008) Buried water molecules in helical transmembrane proteins. Protein Sci 17:293–298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Buss V, Sugihara M, Entel P et al (2003) Thr94 and Wat2b effect protonation of the retinal chromophore in rhodopsin. Angew Chem Int Ed Engl 42:3245–3247

    Article  CAS  PubMed  Google Scholar 

  71. Jastrzebska B, Palczewski K, Golczak M (2011) Role of bulk water in hydrolysis of the rhodopsin chromophore. J Biol Chem 286:18930–18937

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Padayatti PS, Wang L, Gupta S et al (2013) A hybrid structural approach to analyze ligand binding by the serotonin type 4 receptor (5-HT4). Mol Cell Proteomics 12:1259–1271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Angel TE, Gupta S, Jastrzebska B et al (2009) Structural waters define a functional channel mediating activation of the GPCR, rhodopsin. Proc Natl Acad Sci U S A 106:14367–14372

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Hofmann KP, Scheerer P, Hildebrand PW et al (2009) A G protein-coupled receptor at work: the rhodopsin model. Trends Biochem Sci 34:540–552

    Article  CAS  PubMed  Google Scholar 

  75. Angel TE, Chance MR, Palczewski K (2009) Conserved waters mediate structural and functional activation of family A (rhodopsin-like) G protein-coupled receptors. Proc Natl Acad Sci U S A 106:8555–8560

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Fritze O, Filipek S, Kuksa V et al (2003) Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activation. Proc Natl Acad Sci U S A 100:2290–2295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Dryja TP, McGee TL, Reichel E et al (1990) A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343:364–366

    Article  CAS  PubMed  Google Scholar 

  78. Nathans J (1992) Rhodopsin: structure, function, and genetics. Biochemistry 31:4923–4931

    Article  CAS  PubMed  Google Scholar 

  79. Malanson KM, Lem J (2009) Rhodopsin-mediated retinitis pigmentosa. Prog Mol Biol Transl Sci 88:1–31

    Article  CAS  PubMed  Google Scholar 

  80. Rosenfeld PJ, Cowley GS, McGee TL et al (1992) A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nat Genet 1:209–213

    Article  CAS  PubMed  Google Scholar 

  81. Kumaramanickavel G, Maw M, Denton MJ et al (1994) Missense rhodopsin mutation in a family with recessive RP. Nat Genet 8:10–11

    Article  CAS  PubMed  Google Scholar 

  82. Hamel C (2006) Retinitis pigmentosa. Orphanet J Rare Dis 1:40

    Article  PubMed Central  PubMed  Google Scholar 

  83. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809

    Article  CAS  PubMed  Google Scholar 

  84. Jastrzebska B, Ringler P, Lodowski DT et al (2011) Rhodopsin-transducin heteropentamer: three-dimensional structure and biochemical characterization. J Struct Biol 176:387–394

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Sekharan S, Morokuma K (2011) QM/MM study of the structure, energy storage, and origin of the bathochromic shift in vertebrate and invertebrate bathorhodopsins. J Am Chem Soc 133:4734–4737

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Gonzalez-Luque R, Garavelli M, Bernardi F et al (2000) Computational evidence in favor of a two-state, two-mode model of the retinal chromophore photoisomerization. Proc Natl Acad Sci U S A 97:9379–9384

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Mertz B, Struts AV, Feller SE et al (2012) Molecular simulations and solid-state NMR investigate dynamical structure in rhodopsin activation. Biochim Biophys Acta 1818:241–251

    Article  CAS  PubMed  Google Scholar 

  88. Liang Y, Fotiadis D, Maeda T et al (2004) Rhodopsin signaling and organization in heterozygote rhodopsin knockout mice. J Biol Chem 279:48189–48196

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Fotiadis D, Liang Y, Filipek S et al (2003) Atomic-force microscopy: rhodopsin dimers in native disc membranes. Nature 421:127–128

    Article  CAS  PubMed  Google Scholar 

  90. Park PS, Filipek S, Wells JW et al (2004) Oligomerization of G protein-coupled receptors: past, present, and future. Biochemistry 43:15643–15656

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Comar WD, Schubert SM, Jastrzebska B et al (2014) Time-resolved fluorescence spectroscopy measures clustering and mobility of a G protein-coupled receptor opsin in live cell membranes. J Am Chem Soc 136:8342–8349

    Article  CAS  PubMed  Google Scholar 

  92. Fotiadis D, Jastrzebska B, Philippsen A et al (2006) Structure of the rhodopsin dimer: a working model for G-protein-coupled receptors. Curr Opin Struct Biol 16:252–259

    Article  CAS  PubMed  Google Scholar 

  93. Jastrzebska B, Orban T, Golczak M et al (2013) Asymmetry of the rhodopsin dimer in complex with transducin. FASEB J 27:1572–1584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Sakami S, Maeda T, Bereta G et al (2011) Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations. J Biol Chem 286:10551–10567

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Sakami S, Kolesnikov AV, Kefalov VJ et al (2013) P23H opsin knock-in mice reveal a novel step in retinal rod disc morphogenesis. Hum Mol Genet 23:1723–1741

    Article  PubMed  Google Scholar 

  96. Zhang N, Kolesnikov AV, Jastrzebska B et al (2013) Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization. J Clin Invest 123:121–137

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Leslie T. Webster, Jr., and the members of Palczewski’s laboratory for their comments on the manuscript. The work was supported by funding from the National Eye Institute, National Institutes of Health Grants R01EY008061 (to K.P.). K.P. is the John H. Hord Professor of Pharmacology.

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Correspondence to Krzysztof Palczewski Ph.D. .

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Hofmann, L., Palczewski, K. (2015). The G Protein-Coupled Receptor Rhodopsin: A Historical Perspective. In: Jastrzebska, B. (eds) Rhodopsin. Methods in Molecular Biology, vol 1271. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2330-4_1

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  • DOI: https://doi.org/10.1007/978-1-4939-2330-4_1

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