Deciphering the Evolution of G Protein-Coupled Receptors in Vertebrates

  • Craig W. StevensEmail author
Part of the Neuromethods book series (NM, volume 60)


G protein-coupled receptors (GPCRs) are ancestrally related membrane proteins on cells that mediate the pharmacological effect of most drugs and neurotransmitters. GPCRs are the largest group of membrane receptor proteins encoded in the human genome. Using the case study of vertebrate opioid receptors, this chapter introduces an evolutionary approach to understanding pharmacological selectivity, predicted from sequence analysis, and confirmed by experimental studies. The same approach can be used to examine receptor function and applies to other families of GPCRs besides the opioid receptor family. Opioid receptors consist of a family of four closely related proteins expressed in all vertebrates examined. The three types of opioid receptors shown unequivocally to mediate analgesia in animal models and in humans are the mu (MOR), delta (DOR), and kappa (KOR) opioid receptor proteins. The role of the fourth member of the opioid receptor family, the nociceptin or orphanin FQ receptor (ORL), in producing analgesia is not as clear. There are now cDNA sequences for all four types of opioid receptors that are expressed in the brain of six species from three different classes of vertebrates. This chapter presents a comparative analysis of vertebrate opioid receptors using bioinformatics and data from recent human genome studies. Results indicate that opioid receptor genes most likely arose by gene duplication, that there appears to be an evolutionary vector of opioid receptor type divergence in sequence and function, and that the hMOR gene shows evidence of positive selection or adaptive evolution in Homo sapiens. Additionally, unlike many typical reviews, this paper highlights the methods used to come to these conclusions.

Key words

Opioid receptors Molecular evolution Bioinformatics Positive selection Gene duplication 



The author gratefully acknowledges the past and continued support of the National Institutes of Health-NIDA through research grants DA R15-12448 and DA R29-07326, as well as the state of Oklahoma through the Oklahoma Center for the Advancement of Science and Technology (OCAST) Health Research Contracts. Many thanks also to my colleagues at the International Narcotics Research Conference ( for their encouragement and inspiration. This chapter is dedicated to my children in celebration of their entry into adulthood.


  1. 1.
    Attwood TK (2001) A compendium of specific motifs for diagnosing GPCR subtypes. Trends Pharmacol Sci 22:162–165.PubMedGoogle Scholar
  2. 2.
    Perez DM (2003) The evolutionarily triumphant G-protein-coupled receptor. Mol Pharmacol 63:1202–1205.PubMedGoogle Scholar
  3. 3.
    Perez DM (2005) From plants to man: the GPCR “tree of life”. Mol Pharmacol 67:1383–1384.PubMedGoogle Scholar
  4. 4.
    Bockaert J, Pin JP (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. The EMBO Journal 18:1723–1729.PubMedGoogle Scholar
  5. 5.
    Fredriksson R, Lagerstrom MC, Lundin LG et al (2003) The G-protein-coupled receptors in the human genome form five main families: Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272.PubMedGoogle Scholar
  6. 6.
    Fredriksson R, Schiotch H.B. (2005) The ­repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol 67:1414–1425.PubMedGoogle Scholar
  7. 7.
    Josefsson L-G (2000) Evidence for kinship between diverse G-protein coupled receptors. Gene 239:333–340.Google Scholar
  8. 8.
    Sundstrom G, Dreborg S, Larhammar D (2010) Concomitant duplications of opioid peptide and receptor genes before the origin of jawed vertebrates. PLoS One 5:e10512.PubMedGoogle Scholar
  9. 9.
    Dreborg S, Sundstrom G, Larsson TA et al (2008) Evolution of vertebrate opioid receptors. Proc Natl Acad Sci USA 105:15487–15492.PubMedGoogle Scholar
  10. 10.
    Cavalier-Smith T (1998) A revised six-­kingdom system of life. Biol Rev Camb Philos Soc 73:203–266.PubMedGoogle Scholar
  11. 11.
    Iyer LM, Balaji S, Koonin EV et al (2006) Evolutionary genomics of nucleo-cytoplasmic large DNA viruses. Virus Res 117:156–184.PubMedGoogle Scholar
  12. 12.
    Bamford DH (2003) Do viruses form lineages across different domains of life? Res Microbiol 154:231–236.PubMedGoogle Scholar
  13. 13.
    Maussang D, Vischer HF, Schreiber A et al (2009) Pharmacological and biochemical characterization of human cytomegalovirus-encoded G protein-coupled receptors. Methods Enzymol 460:151–171.PubMedGoogle Scholar
  14. 14.
    Maussang D, Vischer HF, Leurs R et al (2009) Herpesvirus-encoded G protein-coupled receptors as modulators of cellular function. Mol Pharmacol 76:692–701.PubMedGoogle Scholar
  15. 15.
    Taylor EW, Agarwal A (1993) Sequence homology between bacteriorhodopsin and G-protein coupled receptors: exon shuffling or evolution by duplication? FEBS Lett 325:161–166.PubMedGoogle Scholar
  16. 16.
    Martin WR, Eades CG, Thompson JA et al (1976) The effects of morphine-and ­nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532.PubMedGoogle Scholar
  17. 17.
    Lord JAH, Waterfield AA, Hughes J et al (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499.PubMedGoogle Scholar
  18. 18.
    Portoghese PS, Sultana M, Takemori AE (1988) Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist. Eur J Pharm 146:185–186.Google Scholar
  19. 19.
    Takemori AE, Ho BY, Naeseth JS et al (1988) Nor-binaltorphimine, a highly selective kappa-opioid antagonist in analgesic and receptor binding assays. J Pharmacol Exp Ther 246:255–258.PubMedGoogle Scholar
  20. 20.
    Ward SJ, Portoghese PS, Takemori AE (1982) Pharmacological profiles of beta-funaltrexamine (β-FNA) and beta-chlornaltrexamine (β-CNA) on the mouse vas deferens preparation. Eur J Pharmacol 80:377–384.PubMedGoogle Scholar
  21. 21.
    Pert CB, Snyder SH (1973) Opiate receptor: demonstration in nervous tissue. Science 179:1011–1014.PubMedGoogle Scholar
  22. 22.
    Simon EJ, Hiller JM, Edelman I (1973) Stereospecific binding of the potent narcotic analgesic [3H] etorphine to rat-brain homogenate. Proc Natl Acad Sci USA 70:1947–1949.PubMedGoogle Scholar
  23. 23.
    Terenius L (1973) Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol Toxicol 32:317–320.Google Scholar
  24. 24.
    Loh H, Smith A (1990) Molecular characterization of opioid receptors. Ann Rev Pharmacol Toxicol 30:123–147.Google Scholar
  25. 25.
    Simon EJ (1986) Recent studies on opioid receptors: heterogeneity and purification. Annal NY Acad Sci 463:31–45.Google Scholar
  26. 26.
    Simon EJ (1981) Opiate receptors: some recent developments. In: Lamble JW (ed) Towards Understanding Receptors, Elsevier/North-Holland Biomedical Press, New York.Google Scholar
  27. 27.
    Zaki PA, Bilsky EJ, Vanderah TW et al (1996) Opioid receptor types and subtypes: The delta receptor as a model. Ann Rev Pharmacol Toxicol 36:379–401.Google Scholar
  28. 28.
    Wollemann M, Benyhe S, Simon J (1993) The kappa opioid receptor: evidence for the different subtypes. Life Sci 52:599–611.PubMedGoogle Scholar
  29. 29.
    Kieffer BL, Befort K, Gaveriaux-Ruff C et al (1992) The delta-opioid receptor: Isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA 89:12048–12052.PubMedGoogle Scholar
  30. 30.
    Evans CJ, Keith DE, Morrison H et al (1992) Cloning of a delta opioid receptor by functional expression. Science 258:1952–1955.PubMedGoogle Scholar
  31. 31.
    Wang JB, Johnson PS, Persico AM et al (1994) Human mu opiate receptor. cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett 338:217–222.PubMedGoogle Scholar
  32. 32.
    Knapp RJ, Malatynska E, Fang L et al (1994) Identification of a human delta opioid receptor: cloning and expression. Life Sci 54:L463–L469.Google Scholar
  33. 33.
    Simonin F, Befort K, Gaveriaux-Ruff C et al (1994) The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain. Mol Pharmacol 46:1015–1021.PubMedGoogle Scholar
  34. 34.
    Mansson E, Bare L, Yang D (1994) Isolation of a human kappa opioid receptor cDNA from placenta. Biochem Biophys Res Commun 202:1431–1437.PubMedGoogle Scholar
  35. 35.
    Zhu J, Chen C, Xue JC et al (1995) Cloning of a human kappa opioid receptor from the brain. Life Sci 56:L201–L207.Google Scholar
  36. 36.
    Simonin F, Gaveriaux-Ruff C, Befort K et al (1995) Kappa-opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA 92:7006–7010.PubMedGoogle Scholar
  37. 37.
    Mollereau C, Parmentier M, Mailleux P et al (1994) ORL1, a novel member of the opioid receptor family: cloning, functional expression and localization. FEBS Lett 341:33–38.PubMedGoogle Scholar
  38. 38.
    Fukuda K, Kato S, Mori K et al (1994) cDNA cloning and regional distribution of a novel member of the opioid receptor family. FEBS 343:42–46.Google Scholar
  39. 39.
    Chen Y, Fan Y, Liu J et al (1994) Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family. FEBS Lett 347:279–283.PubMedGoogle Scholar
  40. 40.
    Bunzow JR, Saez C, Mortrud M et al (1994) Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta, or kappa opioid receptor type. FEBS Letters 347:284–288.PubMedGoogle Scholar
  41. 41.
    Wang JB, Johnson PS, Imai Y et al (1994) cDNA cloning of an orphan opiate receptor gene family member and its splice variant. FEBS Lett 348:75–79.PubMedGoogle Scholar
  42. 42.
    Lachowicz JE, Shen Y, Monsma FJ Jr, et al (1995) Molecular cloning of a novel G ­protein-coupled receptor related to the opiate receptor family. J Neurochem 64:34–40.PubMedGoogle Scholar
  43. 43.
    Wick MJ, Minnerath SR, Lin X et al (1994) Isolation of a novel cDNA encoding a putative membrane receptor with high homology to the cloned mu, delta, and kappa opioid receptors. Brain Res 27:37–44.Google Scholar
  44. 44.
    Meunier J-C, Mollereau C, Toll L et al (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–535.PubMedGoogle Scholar
  45. 45.
    Reinscheid RK, Nothacker HP, Bourson A et al (1995) Orphanin FQ: a neuropeptide that activates an opioid-like G protein-coupled receptor. Science 270:792–794.PubMedGoogle Scholar
  46. 46.
    Meunier J-C (1997) Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor. Eur J Pharmacol 340:1–15.PubMedGoogle Scholar
  47. 47.
    Mogil JS, Pasternak G (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53:381–415.PubMedGoogle Scholar
  48. 48.
    Chen X, Liu-Chen LY, Tallarida RJ et al (1996) Use of a mu-antisense oligodeoxynucleotide as a mu opioid receptor noncompetitive antagonist in vivo. Neurochem Res 21:1363–1368.PubMedGoogle Scholar
  49. 49.
    Wang HQ, Kampine JP, Tseng L-F (1996) Antisense oligodeoxynucleotide to a delta-opioid receptor messenger RNA selectively blocks the antinociception induced by intracerebroventricularly administered delta-, but not mu-, or kappa-opioid receptor agonists in the mouse. Neurosci 75:445–452.PubMedGoogle Scholar
  50. 50.
    Pasternak GW, Standifer KM (1995) Mapping of opioid receptors using antisense oligodeoxynucleotides: correlating their molecular biology and pharmacology. Trends Pharmacol Sci 16:344–350.PubMedGoogle Scholar
  51. 51.
    Uhl GR, Childers S, Pasternak G (1994) An opiate-receptor gene family reunion. Trends Neurosci 17:89–93.PubMedGoogle Scholar
  52. 52.
    Pan Y-X, Xu J, Bolan E et al (1999) Identification and characterization of three new alternatively spliced mu-opioid receptor isoforms. Mol Pharmacol 56:396–403.PubMedGoogle Scholar
  53. 53.
    Pan Y-X, Cheng J, Xu J et al (1995) Cloning and functional characterization through antisense mapping of a kappa 3-related opioid receptor. Mol Pharmacol 47:1180–1188.PubMedGoogle Scholar
  54. 54.
    Pasternak GW (2005) Molecular biology of opioid analgesia. J Pain Symptom Manag 29:S2–S9.Google Scholar
  55. 55.
    Pan YX, Xu J, Bolan E et al (2005) Identification of four novel exon 5 splice variants of the mouse mu-opioid receptor gene: functional consequences of C-terminal splicing. Mol Pharmacol 68:866–875.PubMedGoogle Scholar
  56. 56.
    Pan YX, Xu J, Mahurter L et al (2003) Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun 301:1057–1061.PubMedGoogle Scholar
  57. 57.
    Gaveriaux-Ruff C, Peluso J, Befort K et al (1997) Detection of opioid receptor mRNA by RT-PCR reveals alternative splicing for the delta- and kappa-opioid receptors. Mol Brain Res 48:298–304.PubMedGoogle Scholar
  58. 58.
    Wei LN, Law PY, Loh HH (2004) Post-transcriptional regulation of opioid receptors in the nervous system. Front Biosci 9:1665–1679.PubMedGoogle Scholar
  59. 59.
    Pan YX, Xu J, Wan BL et al (1998) Identification and differential regional expression of KOR-3/ORL-1 gene splice variants in mouse brain. FEBS Lett 435:65–68.PubMedGoogle Scholar
  60. 60.
    Stevens CW, Pezalla PD (1983) A spinal site mediates opiate analgesia in frogs. Life Sci 33:2097–2103.PubMedGoogle Scholar
  61. 61.
    Stevens CW, Pezalla PD (1984) Naloxone blocks the analgesic action of levorphanol but not of dextrorphan in the leopard frog. Brain Res 301:171–174.PubMedGoogle Scholar
  62. 62.
    Pezalla PD, Stevens CW (1984) Behavioral effects of morphine, levorphanol, dextrorphan and naloxone in the frog Rana pipiens. Pharmacol Biochem Behav 21:213–217.PubMedGoogle Scholar
  63. 63.
    Stevens CW, Pezalla PD, Yaksh TL (1987) Spinal antinociceptive action of three representative opioid peptides in frogs. Brain Res 402:201–203.PubMedGoogle Scholar
  64. 64.
    Stevens CW, Kirkendall K (1993) Time course and magnitude of tolerance to the analgesic effects of systemic morphine in amphibians. Life Sci 52:PL111–116.Google Scholar
  65. 65.
    Pezalla PD, Dicig M (1984) Stress-induced analgesia in frogs: evidence for the involvement of an opioid system. Brain Res 296:356–360.PubMedGoogle Scholar
  66. 66.
    Stevens CW, Sangha S, Ogg BG (1995) Analgesia produced by immobilization stress and an enkephalinase-inhibitor in amphibians. Pharmacol Biochem Behav 51:675–680.PubMedGoogle Scholar
  67. 67.
    Willenbring S, Stevens CW (1996) Thermal, mechanical and chemical peripheral sensation in amphibians: opioid and adrenergic effects. Life Sci 58:125–133.PubMedGoogle Scholar
  68. 68.
    Willenbring S, Stevens CW (1997) Spinal mu, delta and kappa opioids alter chemical, mechanical and thermal sensitivities in amphibians. Life Sci 61:2167–2176.PubMedGoogle Scholar
  69. 69.
    Mohan S, Stevens CW (2006) Systemic and spinal administration of the mu opioid, remifentanil, produces antinociception in amphibians. Eur J Pharmacol 534:89–94.PubMedGoogle Scholar
  70. 70.
    Stevens CW, Toth G, Borsodi A et al (2007) Xendorphin B1, a novel opioid-like peptide determined from a Xenopus laevis brain cDNA library, produces opioid antinociception after spinal administration in amphibians. Brain Res Bull 71:628–632.PubMedGoogle Scholar
  71. 71.
    Stevens CW, Klopp AJ, Facello JA (1994) Analgesic potency of mu and kappa opioids after systemic administration in amphibians. J Pharmacol Exp Ther 269:1086–1093.PubMedGoogle Scholar
  72. 72.
    Stevens CW (1996) Relative analgesic potency of mu, delta and kappa opioids after spinal administration in amphibians. J Pharmacol Exp Ther 276:440–448.PubMedGoogle Scholar
  73. 73.
    Stevens CW, Rothe KS (1997) Supraspinal administration of opioids with selectivity for mu, delta and kappa -opioid receptors produces analgesia in amphibians. Eur J Pharmacol 331:15–21.PubMedGoogle Scholar
  74. 74.
    Stevens CW (2004) Opioid research in amphibians: an alternative pain model yielding insights on the evolution of opioid receptors. Brain Res Rev 46:204–215.PubMedGoogle Scholar
  75. 75.
    Stevens, C. W. (2008) Non-mammalian models for the study of pain. In: Conn PM (ed) Sourcebook of Models for Biomedical Research, Humana Press, Totowa.Google Scholar
  76. 76.
    Stevens CW, Martin KK, Stahlheber BW (2008) Nociceptin produces antinoci­ception after spinal administration in amphibians. Pharmacol Biochem Behav 91:436–440.PubMedGoogle Scholar
  77. 77.
    Stevens CW, Newman LC (1999) Spinal administration of selective opioid antagonists in amphibians: evidence for an opioid unireceptor. Life Sci 64:PL125–PL130.Google Scholar
  78. 78.
    Gonzalez-Nunez V, Barrallo A, Traynor JR et al (2006) Characterization of opioid binding sites in zebrafish brain. J Pharmacol Exp Ther 316:900–904.PubMedGoogle Scholar
  79. 79.
    Brooks AI, Standifer KM, Cheng J et al (1994) Opioid binding in giant toad and goldfish brain. Receptor 4:55–62.PubMedGoogle Scholar
  80. 80.
    Bird DJ, Jackson M, Baker BI et al (1988) Opioid binding sites in the fish brain: An autoradiographic study. Gen Comp Endocrinol 70:49–62.PubMedGoogle Scholar
  81. 81.
    Buatti MC, Pasternak GW (1981) Multiple opiate receptors: phylogenetic differences. Brain Res 218:400–405.PubMedGoogle Scholar
  82. 82.
    Simon EJ, Hiller JM, Groth J et al (1982) The nature of opiate receptors in toad brain. Life Sci 31:1367–1370.PubMedGoogle Scholar
  83. 83.
    Zawilska J, Lajtha A, Borsodi A (1988) Selective protection of benzomorphan binding sites against inactivation by N-ethylmaleimide: Evidence for kappa opioid receptors in frog brain. J Neurochem 51:736–739.PubMedGoogle Scholar
  84. 84.
    Benyhe S, Varga E, Hepp J et al (1990) Characterization of kappa1 and kappa2 opioid binding sites in frog (Rana esculenta) brain membrane. Neurochem Res 15:899–904.PubMedGoogle Scholar
  85. 85.
    Simon J, Benyhe S, Hepp J et al (1987) Purification of kappa-opioid receptor subtype from frog brain. Neuropeptides 10:19–28.PubMedGoogle Scholar
  86. 86.
    Simon J, Benyhe S, Borsodi A et al (1985) Separation of kappa-opioid receptor subtype from frog brain. FEBS Letters 183:395–397.PubMedGoogle Scholar
  87. 87.
    Pert CB, Aposhian D, Snyder SH (1974) Phylogenetic distribution of opiate binding. Brain Res 75:356–361.PubMedGoogle Scholar
  88. 88.
    Xia Y, Haddad GG (2001) Major difference in the expression of delta- and mu-opioid receptors between turtle and rat brain. J Comp Neurol 436:202–210.PubMedGoogle Scholar
  89. 89.
    Bakalkin GY, Pivovarov AS, Kobylyansky AG et al (1989) Lateralization of opioid receptors in turtle visual cortex. Brain Res 480:268–276.PubMedGoogle Scholar
  90. 90.
    Benyhe S, Monory K, Farkas J et al (1999) Nociceptin binding sites in frog (Rana esculenta) brain membranes. Biochem Biophys Res Commun 260:592–596.PubMedGoogle Scholar
  91. 91.
    Wollemann M, Farkas J, Toth G et al (1999) Comparison of the endogenous heptapeptide met-enkephalin-arg6-phe7 binding in amphibian and mammalian brain. Acta Biologica Hungarica 50:297–307.PubMedGoogle Scholar
  92. 92.
    Benyhe S, Ketevan A, Simon J et al (1997) Affinity labelling of frog brain opioid receptors by dynorphin(1–10) chloromethyl ketone. Neuropeptides 31:52–59.PubMedGoogle Scholar
  93. 93.
    Moitra J, Öktem HA, Borsodi A (1995) Thermodynamic parameters of frog brain kappa-opioid receptors. J Neurochem 65:798–801.PubMedGoogle Scholar
  94. 94.
    Benyhe S, Simon J, Borsodi A et al (1994) [3H]Dynorphin 1–8 binding sites in frog (Rana esculenta) brain membranes. Neuropeptides 26:359–364.PubMedGoogle Scholar
  95. 95.
    Wollemann M, Farkas J, Toth G et al (1994) Characterization of [3H] met-­enkephalin-arg6-phe7 binding to opioid receptors in frog brain membrane preparations. J Neurochem 63:1460–1465.PubMedGoogle Scholar
  96. 96.
    Benyhe S, Szucs M, Borsodi A et al (1992) Species differences in the stereoselectivity of kappa opioid binding sites for [3H]U-69593 and [3H] ethylketocyclazocine. Life Sci 51:1647–1655.PubMedGoogle Scholar
  97. 97.
    Simon J, Benyhe S, Hepp J et al (1990) Method for isolation of kappa-opioid binding sites by dynorphin affinity chromatography. J Neurosci Res 25:549–555.PubMedGoogle Scholar
  98. 98.
    Mollereau C, Pascaud A, Baillat G et al (1988) Evidence for a new type of opioid binding site in the brain of the frog Rana ridibunda. Eur J Pharmacol 150:75–84.PubMedGoogle Scholar
  99. 99.
    Newman LC, Wallace DR, Stevens CW (2000) Selective opioid agonist and antagonist displacement of [3H]-naloxone binding in amphibian brain. Eur J Pharmacol 397:255–262.PubMedGoogle Scholar
  100. 100.
    Newman LC, Wallace DR, Stevens CW (2000) Selective opioid receptor agonist and antagonist displacement of [3H]-naloxone binding in amphibian spinal cord. Brain Res 884:184–191.PubMedGoogle Scholar
  101. 101.
    Newman LC, Sands SS, Wallace DR et al (2002) Characterization of mu, kappa, and delta opioid binding in amphibian whole brain tissue homogenates. J Pharmacol Exp Ther 301:364–370.PubMedGoogle Scholar
  102. 102.
    Li X, Keith DEJr, Evans CJ (1996) Mu opioid receptor-like sequences are present throughout vertebrate evolution. J Mol Evol 43:179–184.Google Scholar
  103. 103.
    Li X, Keith DE, Jr., Evans CJ (1996) Multiple opioid receptor-like genes are identified in diverse vertebrate phyla. FEBS Lett 397:25–29.PubMedGoogle Scholar
  104. 104.
    Darlison MG, Greten FR, Harvey RJ et al (1997) Opioid receptors from a lower vertebrate (Catostomus commersoni): Sequence, pharmacology, coupling to a G-protein-gated inward-rectifying potassium channel (GIRK1), and evolution. Proc Natl Acad Sci USA 94:8214–8219.PubMedGoogle Scholar
  105. 105.
    Barrallo A, González-Sarmiento R, Porteros A et al (1998) Cloning, molecular characterization, and distribution of a gene homologous to d opioid receptor from zebrafish (Danio rerio). Biochem Biophys Res Commun 245:544–548.PubMedGoogle Scholar
  106. 106.
    Barrallo A, González-Sarmiento R, Alvar F et al (2000) ZFOR2, a new opioid receptor-like gene from the teleost zebrafish (Danio rerio). Mol Brain Res 84:1–6.PubMedGoogle Scholar
  107. 107.
    Alvarez FA, Rodriguez-Martin I, Gonzalez-Nunez V et al (2006) New kappa opioid receptor from zebrafish Danio rerio. Neurosci Lett 405:94–99.PubMedGoogle Scholar
  108. 108.
    Porteros A, Garcia-Isodoro M, Barrallo A et al (1999) Expression of ZFOR1, a delta-opioid receptor, in the central nervous system of the zebrafish (Danio rerio). J Comp Neurol 412:429–438.PubMedGoogle Scholar
  109. 109.
    Bradford CS, Walthers EA, Stanley DJ et al (2006) Delta and mu opioid receptors from the brain of a urodele amphibian, the rough-skinned newt, Taricha granulosa: Cloning, heterologous expression, and pharmacological characterization. Gen Comp Endocrinol 146:275–290.PubMedGoogle Scholar
  110. 110.
    Bradford CS, Walthers EA, Searcy BT et al (2005) Cloning, heterologous expression and pharmacological characterization of a kappa opioid receptor from the brain of the rough-skinned newt, Taricha granulosa. J Mol Endocrinol 34:809–823.PubMedGoogle Scholar
  111. 111.
    Walthers EA, Bradford CS, Moore FL (2005) Cloning, pharmacological characterization and tissue distribution of an ORL1 opioid receptor from an amphibian, the rough-skinned newt, Taricha granulosa. J Mol Endocrinol 34:247–256.PubMedGoogle Scholar
  112. 112.
    Stevens CW, Brasel CM, Mohan S (2007) Cloning and bioinformatics of amphibian mu, delta, kappa, and nociceptin opioid receptors expressed in brain tissue: Evidence for opioid receptor divergence in mammals. Neurosci Lett 419:189–194.PubMedGoogle Scholar
  113. 113.
    Minami M, Satoh M (1995) Molecular ­biology of the opioid receptors: structures, functions and distributions. Neurosci Res 23:121–145.PubMedGoogle Scholar
  114. 114.
    Gether U (2002) Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endo Rev 21:90–113.Google Scholar
  115. 115.
    Shahrestanifar MS, Howells RD (1996) Sensitivity of opioid receptor binding to N-substituted maleimides and methanethiosulfonate derivatives. Neurochem Res 21:1295–1299.PubMedGoogle Scholar
  116. 116.
    Palczewski K, Kumasaka T, Hori T et al (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289:739–746.PubMedGoogle Scholar
  117. 117.
    Lomize AL, Pogozheva ID, Mosberg HI (1999) Structural organization of G-protein-coupled receptors. J Comput Aided Mol Des 13:352–353.Google Scholar
  118. 118.
    Christopoulos A, Kenakin T (2002) G protein-coupled receptor allosterism and complexing. Pharmacol Rev 54:323–374.PubMedGoogle Scholar
  119. 119.
    Wang HL, Chang WT, Hsu CY et al (2002) Identification of two C-terminal amino acids, Ser(355) and Thr(357), required for short-term homologous desensitization of mu-opioid receptors. Biochem Pharmacol 15:257–266.Google Scholar
  120. 120.
    Law P-Y, Wong YH, Loh HH (1999) Mutational analysis of the structure and function of opioid receptors. Biopoly 51:440–455.Google Scholar
  121. 121.
    Ferguson DM, Kramer S, Metzger TG et al (2000) Isosteric replacement of acidic with neutral residues in extracellular loop-2 of the kappa-opioid receptor does not affect dynorphin A(1–13) affinity and function. J Biol Chem 43:1251–1252.Google Scholar
  122. 122.
    Chaturvedi K, Christoffers KH, Singh K et al (2000) Structure and regulation of opioid receptors. Biopolymers 55:334–346.PubMedGoogle Scholar
  123. 123.
    Stevens, C. W. (2005) Molecular evolution of vertebrate opioid receptor proteins: A preview. In Capasso A (ed) Recent Developments in Pain Research, 2005. Research Signpost, Trivandrum.Google Scholar
  124. 124.
    Altschul SF, Gish W, Miller W et al (1990) Basic local alignment search tool. J Mol Biol 215:403–410.PubMedGoogle Scholar
  125. 125.
    Rodríguez RE, Barrallo A, Garcia-Malvar F et al (2000) Characterization of ZFOR1, a putative delta-opioid receptor from the teleost zebrafish. Neurosci Lett 288:207–210.PubMedGoogle Scholar
  126. 126.
    Brasel CM, Sawyer GW, Stevens CW (2008) A pharmacological comparison of the cloned frog and human mu opioid receptors reveals differences in opioid affinity and function. Eur J Pharmacol 599:36–43.PubMedGoogle Scholar
  127. 127.
    Ohno, S (1970) Evolution by Gene Duplication. George Allen and Unwin, London.Google Scholar
  128. 128.
    Lundin LG, Larhammar D, Hallbook F (2003) Numerous groups of chromosomal regional paralogies strongly indicate two genome doublings at the root of the vertebrates. J Struct Funct Genomics 3:53–63.PubMedGoogle Scholar
  129. 129.
    Zhang J (2003) Evolution by gene duplication: an update. Trends Ecol Evol 18:292–298.Google Scholar
  130. 130.
    McLysaght A, Hokamp K, Wolfe KH (2002) Extensive genomic duplication during early chordate evolution. Nat Genet 31:200–204.PubMedGoogle Scholar
  131. 131.
    Hokamp K, McLysaght A, Wolfe KH (2003) The 2R hypothesis and the human genome sequence. J Struct Funct Genomics 3:95–110.PubMedGoogle Scholar
  132. 132.
    Krylov DM, Wolf YI, Rogozin IB et al (2003) Gene loss, protein sequence divergence, gene dispensability, expression level, and interactivity are correlated in eukaryotic evolution. Genome Res 13:2229–2235.PubMedGoogle Scholar
  133. 133.
    Prince VE, Pickett FB (2002) Splitting pairs: the diverging fates of duplicated genes. Nat Rev Genet 3:827–837.PubMedGoogle Scholar
  134. 134.
    Kondrashhov FA, Rogozin IB, Wolf YI et al (2002) Selection in the evolution of gene duplications. Genome Biol 3:0008.1–0008.9.Google Scholar
  135. 135.
    Jordan IK, Wolf YI, Koonin EV (2004) Duplicated genes evolve slower than singletons despite the initial rate increase. BMC Evol Biol 4:22.PubMedGoogle Scholar
  136. 136.
    Makalowski W (2001) Are we polyploids? A brief history of one hypothesis. Genome Res 11:667–670.PubMedGoogle Scholar
  137. 137.
    Hoehe MR (2003) Haplotypes and the systematic analysis of genetic variation in genes and genomes. Pharmacogenomics 4:547–570.PubMedGoogle Scholar
  138. 138.
    Rommelspacher H, Smolka M, Schmidt LG et al (2001) Genetic analysis of the mu-­opioid receptor in alcohol-dependent individuals. Alcohol 24:129–135.PubMedGoogle Scholar
  139. 139.
    LaForge KS, Yuferov V, Kreek MJ (2000) Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur J Pharmacol 410:249–268.PubMedGoogle Scholar
  140. 140.
    Bond C, LaForge KS, Tian M et al (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 95:9608–9613.PubMedGoogle Scholar
  141. 141.
    Hoehe MR, Kopke K, Wendel B et al (2000) Sequence variability and candidate gene analysis in complex disease: association of mu ­opioid receptor gene variation with substance dependence. Hum Mol Genet 9:2895–2908.PubMedGoogle Scholar
  142. 142.
    Mayer P, Hollt V (2006) Pharmacogenetics of opioid receptors and addiction. Pharm Genomics 16:1–7.Google Scholar
  143. 143.
    Klepstad P, Dale O, Skorpen F et al (2005) Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand 49:902–908.PubMedGoogle Scholar
  144. 144.
    Bayerer B, Stamer U, Hoeft A et al (2007) Genomic variations and transcriptional regulation of the human mu-opioid receptor gene. Eur J Pain 11:421–427.PubMedGoogle Scholar
  145. 145.
    Uhl GR, Sora I, Wang Z (1999) The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci USA 96:7752–7755.PubMedGoogle Scholar
  146. 146.
    Gu J, Gu X (2003) Induced gene expression in human brain after the split from chimpanzee. Trends Genet 19:63–65.PubMedGoogle Scholar
  147. 147.
    Jordan IK, Marino-Ramirez L, Koonin EV (2005) Evolutionary significance of gene expression divergence. Gene 345:119–126.PubMedGoogle Scholar
  148. 148.
    Yuferov V, Fussell D, LaForge KS et al (2004) Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics 14:793–804.PubMedGoogle Scholar
  149. 149.
    Saito M, Ehringer MA, Toth R et al (2003) Variants of kappa-opioid receptor gene and mRNA in alcohol-preferring and alcohol-avoiding mice. Alcohol 29:39–49.PubMedGoogle Scholar
  150. 150.
    Kobayashi H, Hata H, Ujike H et al (2006) Association analysis of delta-opioid receptor gene polymorphisms in methamphetamine dependence/psychosis. Am J Med Genet B Neuropsychiatr Genet 141:482–486.Google Scholar
  151. 151.
    Ito E, Xie GX, Maruyama K et al (2000) A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5’-adjacent gene GAIP. J Mol Biol 304:259–270.PubMedGoogle Scholar
  152. 152.
    Clark AG, Hubisz MJ, Bustamante CD et al (2005) Ascertainment bias in studies of human genome-wide polymorphism. Genome Research 15:1496–1502.PubMedGoogle Scholar
  153. 153.
    Iwama H, Gojobori T (2002) Identification of neurotransmitter receptor genes under significantly relaxed selective constraint by orthologous gene comparisons between humans and rodents. Mol Biol Evol 19:1891–1901.PubMedGoogle Scholar
  154. 154.
    Rana BK, Hewett-Emmett D, Jin L et al (1999) High polymorphism at the human melanocortin 1 receptor locus. Genetics 151:1547–1557.PubMedGoogle Scholar
  155. 155.
    McPartland JM, Norris RW, Kilpatrick CW (2007) Tempo and mode in the endocannaboinoid system. J Mol Evol 65:267–276.PubMedGoogle Scholar
  156. 156.
    Ikeda K, Ide S, Han W et al (2005) How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 26:311–317.PubMedGoogle Scholar
  157. 157.
    Merritt TJ, Quattro JM (2001) Evidence for a period of directional selection following gene duplication in a neurally expressed locus of triosephosphate isomerase. Genetics 159:689–697.PubMedGoogle Scholar
  158. 158.
    Dorus S, Vallender EJ, Evans PD et al (2004) Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119:1027–1040.PubMedGoogle Scholar
  159. 159.
    Wolfe KH, Li WH (2003) Molecular evolution meets the genomics revolution. Nat Genet 33:255–265.PubMedGoogle Scholar
  160. 160.
    Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680.PubMedGoogle Scholar
  161. 161.
    Kumar S, Tamura K, Nei M (2004) MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform 5:150–163.PubMedGoogle Scholar
  162. 162.
    Zhang J, Nei M (1997) Accuracies of ancestral amino acid sequences inferred by the parsimony, likelihood, and distance methods. J Mol Evol 44:S139–S146.PubMedGoogle Scholar
  163. 163.
    Madsen O, Willemsen D, Ursing B et al (2002) Molecular evolution of the mammalian alpha 2B adrenergic receptor. Mol Biol Evol 19:2150–2160.PubMedGoogle Scholar
  164. 164.
    Ortlund EA, Bridgham JT, Redinbo MR et al (2007) Crystal structure of an ancient protein: evolution by conformational epistasis. Science 317:1544–1548.PubMedGoogle Scholar
  165. 165.
    Madabushi S, Gross AK, Philippi A et al (2004) Evolutionary trace of G protein-­coupled receptors reveals clusters of residues that determine global and class-specific functions. J Bio Chem 279:8126–8132.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pharmacology and Physiology, College of Osteopathic MedicineOklahoma State University-Center for Health SciencesTulsaUSA

Personalised recommendations