Products of Inflammatory Cells Synergistically Enhance Superoxide Production by Phagocytic Leukocytes

  • John A. Badwey
  • Jiabing Ding
  • Paul G. Heyworth
  • John M. Robinson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 314)


Superoxide (O 2 ) is a major component of the oxygen-dependent antimicrobial and cytocidal arsenal of neutrophils 1, 2. The oxidase system that generates this substance is dormant and disassembled in unstimulated cells and consists of both membrane-bound and soluble (“cytosolic factors”) components3, 4. The known membrane-components are a low-potential, heterodimeric b-cytochrome5, 6 and a ras-related GTP-binding protein7. The most thoroughly characterized cytosolic factors are proteins with molecular masses of 47 (p47) and 67kDa8–11. Upon stimulation of neutrophils, there is a translocation of the soluble components to the plasmalemma where the oxidase is assembled12, 13 (Figure 1). This assembly requires the presence of the b-cytochrome12, 14 and is associated with and/or organized by cytoskeletal proteins15. The intact system produces O 2 according to the following stoichiometry:
$${\rm{NAPDH + 2}}{{\rm{0}}_{\rm{2}}} \to {\rm{2}}{{\rm{0}}_{\rm{2}}}^{\rm{ - }}{\rm{ + NAD}}{{\rm{P}}^{\rm{ + }}}{\rm{ + 2}}{{\rm{H}}^{\rm{ + }}}{\rm{.}}$$


Human Neutrophil Phorbol Ester Chronic Granulomatous Disease Calcium Ionophore A23187 Superoxide Release 
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  1. 1.
    J. A. Badwey, and M. L. Karnovsky, Active oxygen species and the functions of phagocytic leukocytes, Annu. Rev. Biochem. 49: 695 (1980).PubMedCrossRefGoogle Scholar
  2. 2.
    J. T. Curnutte and B. M. Babior, Chronic granulomatous disease, Adv. Human Genet. 16: 229 (1987).Google Scholar
  3. 3.
    R. A. Heyneman and R. E. Vercauteren, Activation of a NADPH-oxidase from horse polymorphonuclear leukocytes in a cell-free system, J. Leukocyte Biol. 36: 751 (1984).PubMedGoogle Scholar
  4. 4.
    Y. Bromberg and E. Pick, Unsaturated fatty acids stimulate NADPH-dependent superoxide production by cell free system derived from macrophages, Cell Immunol. 88: 213 (1984).PubMedCrossRefGoogle Scholar
  5. 5.
    A. W. Segal and O. T. Jones, Novel cytochrome b system in phagocytic vacuoles from human granules, Nature 276: 515 (1978).PubMedCrossRefGoogle Scholar
  6. 6.
    C. A. Parkos, R. A. Allen, C. G. Cochrane, and A. J. Jesaitis, Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000, J. Clin. Invest. 80: 73 (1987).CrossRefGoogle Scholar
  7. 7.
    M. T. Quinn, C. A. Parkos, L. Walker, S. H. Grkin, M. C. Dinauer, and A. J. Jesaitis, Association of a Ras-related protein with cytochrome b of human neutrophils, Nature 342: 198 (1989).PubMedCrossRefGoogle Scholar
  8. 8.
    B. D. Volpp, W. M. Nauseef, and R. A. Clark, Two cytosolic neutrophil oxidase components absent in autosomal chronic granulomatous disease, Science 242: 1295 (1988).PubMedCrossRefGoogle Scholar
  9. 9.
    H. Nunoi, D. Rotrosen, J. I. Gallin, and H. L. Malech, Two forms of autosomal chronic granulomatous disease are deficient in distinct neutrophil cytosol factors, Science 242: 1298 (1988).PubMedCrossRefGoogle Scholar
  10. 10.
    B. D. Volpp, W. M. Nauseef, J. E. Donelson, D. R. Moser, and R. A. Clark, Cloning of the cDNA and functional expression of the 47-kilodalton cytosolic component of human neutrophil respiratory burst oxidase, Proc. Natl. Acad. Sci. USA 86: 7195 (1989).PubMedCrossRefGoogle Scholar
  11. 11.
    T. L. Leto, K. J. Lomax, B. D. Volpp, H. Nunoi, J. M. G. Sechler, W. M. Nauseef, R. A. Clark, J. I. Gallin, and H. L. Malech, Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src, Science 248: 727 (1990).PubMedCrossRefGoogle Scholar
  12. 12.
    P. G. Heyworth, C. F. Shrimpton, and A. W. Segal, Localization of the 47kDa phosphoprotein involved in the respiratory burst oxidase of phagocytic cells, Biochem. J. 260: 243 (1989).PubMedGoogle Scholar
  13. 13.
    R. A. Clark, B. D. Volpp, K. G. Leidal, and W. M. Nauseef, Two cytosolic components of the human respiratory burst oxidase translocate to the plasma membrane during cell activation, J. Clin. Invest. 85: 714 (1990).PubMedCrossRefGoogle Scholar
  14. 14.
    D. Rotrosen, M. E. Kleinberg, H. Nunoi, T. Leto, J. I. Gallin, and H. L. Malech, Evidence for a functional cytoplasmic domain of phagocyte oxidase cytochrome b558, J. Biol. Chem. 265: 8745 (1990).PubMedGoogle Scholar
  15. 15.
    M. T. Quinn, C. A. Parkos, and A. J. Jesaitis, The lateral organization of components of the membrane skeleton and superoxide generation in the plasma membrane of stimulated human neutrophils, Biochim. Biophys. Acta 987: 83 (1989).PubMedCrossRefGoogle Scholar
  16. 16.
    J. A. Badwey, J. M. Robinson, P. G. Heyworth, and J. T. Curnutte, 1, 2-Dioctanoylglycerol can stimulate neutrophils by different mechanisms. Evidence for a pathway that does not involve phosphorylation of p47, J. Biol. Chem. 264: 20676 (1989).PubMedGoogle Scholar
  17. 17.
    J. M. Robinson, P. G. Heyworth, and J. A. Badwey, Utility of staurosporine in uncovering differences in the signal transduction pathways for superoxide production in neutrophils, Biochim. Biophys. Acta 1052: 299 (1990).CrossRefGoogle Scholar
  18. 18.
    A. W. Segal, P. G. Heyworth, S. Cockroft, and M. M. Barrowman, Stimulated neutrophils from patients with autosomal recessive chronic granulomatous disease fail to phosphorylate a Mr-44,000 protein, Nature 316: 547 (1985).PubMedCrossRefGoogle Scholar
  19. 19.
    P. G. Heyworth, and A. W. Segal, Further evidence for involvement of a phosphoprotein in the respiratory burst oxidase of human neutrophils, Biochem. J. 239: 723 (1986).PubMedGoogle Scholar
  20. 20.
    N. Okamura, J. T. Curnutte, R. L. Roberts, and B. M. Babior, Relationship of protein phosphorylation to the activation of the respiratory burst in human neutrophils: defects in the phosphorylation of a group of closely related 48-kDa proteins in two forms of chronic granulomatous disease, J. Biol. Chem. 263: 6777 (1988).PubMedGoogle Scholar
  21. 21.
    K. J. Lomax, T. L. Leto, H. Nunoi, J. I. Gallin, and H. L. Malech, Recombinant 47 kilodalton cytosol factor restores NADPH oxidase in chronic granulomatous disease, Science 246: 987 (1989).PubMedCrossRefGoogle Scholar
  22. 22.
    C. House, R. E. Wettenhall, and B. E. Kemp, The influence of basic residues on the substrate specificity of protein kinase C, J. Biol. Chem. 262: 772 (1987).PubMedGoogle Scholar
  23. 23.
    D. Rotrosen and T. L. Leto, Phosphorylation of neutrophil 47kDa cytosolic oxidase factor. Translocation to membrane is associated with distinct phosphorylation events, J. Biol. Chem. 265: 19910 (1990).PubMedGoogle Scholar
  24. 24.
    R. H. Weisbart, D. W. Golde, S. C. Clark, G. G. Wong, and J. C. Gasson, Human granulocyte-macrophage colony stimulating factor is a neutrophil activator, Nature 314: 361 (1985).PubMedCrossRefGoogle Scholar
  25. 25.
    G. Berton, L. Zeni, M. A. Cassatella, and F. Rossi, Gamma interferon is able to enhance the oxidative metabolism of human neutrophils, Biochem. Biophys. Res. Commun. 138: 1276 (1986).PubMedCrossRefGoogle Scholar
  26. 26.
    K. Ishida, K. Takeshige, and S. Minakami, Endothelin-1 enhances superoxide generation of human neutrophils stimulated by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine, Biochem. Biophys. Res. Commun. 173: 496 (1990).PubMedCrossRefGoogle Scholar
  27. 27.
    L. C. McPhail, C. C. Clayton, and R. Snyderman, The NADPH-oxidase of human polymorphonuclear leukocytes. Evidence for regulation by multiple signals. J. Biol. Chem. 259: 5768 (1984).PubMedGoogle Scholar
  28. 28.
    J. T. O’Flaherty, J. D. Schmitt, and R. L. Wykle, Interactions of arachidonate metabolism on protein kinase C in mediating neutrophil function. Biochem. Biophys. Res. Commun. 127: 916 (1985).PubMedCrossRefGoogle Scholar
  29. 29.
    J. T. O’Flaherty, J. F. Redman, D. P. Jacobson, and A. G. Rossi, Stimulation and priming of protein kinase C translocation by a Ca2+ transient-independent mechanism. Studies in human neutrophils challenged with platelet activating factor and other receptor agonists, J. Biol. Chem. 265: 2169 (1990).Google Scholar
  30. 30.
    P. G. Heyworth and J. A. Badwey, Protein phosphorylation associated with the stimulation of neutrophils. Modulation of superoxide production by protein kinase C and calcium, J. Bioenerg. Biomembr. 22: 1 (1990).PubMedCrossRefGoogle Scholar
  31. 31.
    U. Kikkawa, A. Kishimoto, and Y. Nishizuka, The protein kinase C family: heterogeneity and its implications, Annu. Rev. Biochem. 58: 31 (1989).PubMedCrossRefGoogle Scholar
  32. 32.
    M. Volpi, R. Yassin, P. H. Naccache, and R. I. Sha’afi, Chemotactic factor causes rapid decrease in phosphatidylinositol 4, 5-bisphosphate and phosphatidylinositol 4-monophosphate in rabbit neutrophils, Biochem. Biophys. Res. Commun. 112: 957 (1983).PubMedCrossRefGoogle Scholar
  33. 33.
    C. N. Serhan, M. J. Broekman, H. M. Korchak, J. E. Smolen, A. J. Marcus, and G. Weissman, Changes in phosphatidylinositol and phosphatidic acid in stimulated neutrophils. Relationship to calcium mobilization, aggregation and superoxide radical generation, Biochim. Biophys. Acta 762: 420 (1983).PubMedCrossRefGoogle Scholar
  34. 34.
    H. Ohta, F. Okajima, and M. Ui, Inhibition by islet-activating protein of a chemotactic peptide-induced early breakdown of inositol phospholipids and Ca2+ mobilization in guinea pig neutrophils. J. Biol. Chem. 260: 1571 (1985).Google Scholar
  35. 35.
    J-K. Pai, M. I. Siegel, R. W. Egan, and M. M. Billah, Activation of phospholipase D by chemotactic peptide in HL-60 granulocytes, Biochem. Biophys. Res. Commun. 150: 355 (1988).PubMedCrossRefGoogle Scholar
  36. 36.
    M. Castagna, Y. Takai, K. Kaibuchi, K. Sano, U. Kikkawa, and Y. Nishizuka, Direct activation of calcium activated, phopholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257: 7847 (1982).PubMedGoogle Scholar
  37. 37.
    H. Streb, R. F. Irvine, M. J. Berridge, and I. Schulz, Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-l, 4, 5-trisphosphate, Nature 306: 67 (1983).PubMedCrossRefGoogle Scholar
  38. 38.
    M. Prentki, C. B. Wollheim, and P. D. Lew, Ca2+ homeostasis in permeabilized human neutrophils. Characterization of Ca2+-sequestering pools and the action of inositol-1, 4, 5-trisphosphate. J. Biol. Chem. 25: 1377 (1984).Google Scholar
  39. 39.
    A. Couturier, S. Bazgar, and M. Castagna, Further characterization of tumor-promoter-mediated activation of protein kinase C, Biochem. Biophys. Res. Commun. 121: 448 (1984).PubMedCrossRefGoogle Scholar
  40. 40.
    J. M. Robinson, J. A. Badwey, M. L. Karnovsky, and M. J. Karnovsky, Release of superoxide and change in morphology by neutrophils in response to phorbol esters. Antagonism by inhibitors of calcium binding proteins. J. Cell Biol. 101: 1052 (1985).PubMedCrossRefGoogle Scholar
  41. 41.
    J. A. Badwey, J. M. Robinson, W. Horn, R. J. Soberman, M. J. Karnovsky, and M. L. Karnovsky, Synergistic stimulation of neutrophils. Possible involvement of 5-hydroxy-6, 8, 11, 14-eicosatetraenoate in superoxide release. J. Biol. Chem. 263: 2779 (1988).PubMedGoogle Scholar
  42. 42.
    J. M. Robinson, J. A. Badwey, M. L. Karnovsky, and M. J. Karnovsky, Superoxide release by neutrophils: synergistic effects of a phorbol ester and a calcium ionophore. Biochem. Biophys. Res. Commun. 122: 734 (1984).PubMedCrossRefGoogle Scholar
  43. 43.
    F. Di Virgilio, D. P. Lew, and T. Pozzan, Protein kinase C activation of physiological processes in human neutrophils at vanishingly small cytosolic Ca2+ levels, Nature 310: 691 (1984).PubMedCrossRefGoogle Scholar
  44. 44.
    A. Penfield and M. M. Dale, Synergism between A23187 and 1-oleoyl-2-acetyl-glycerol in superoxide production by human neutrophils, Biochem. Biophys. Res. Commun. 125: 332 (1984).PubMedCrossRefGoogle Scholar
  45. 45.
    T. H. Finkel, M. J. Pabst, H. Suzuki, L. A. Guthrie, J. R. Forehand, W. A. Phillips, and R. B. Johnston Jr., Priming of neutrophils and macrophages for enhanced release of superoxide anion by the calcium ionophore A23187. Implications for regulation of the respiratory burst, J. Biol. Chem. 262: 12589 (1987).PubMedGoogle Scholar
  46. 46.
    K. Kaibuchi, Y. Takai, M. Sawamura, M. Hoshijima, T. Fujikura, and Y. Nishizuka, Synergistic functions of protein phosphorylation and calcium mobilization in platelet activation, J. Biol. Chem. 258: 6701 (1983).PubMedGoogle Scholar
  47. 47.
    W. F. Stenson and C. W. Parker, Metabolism of arachidonic acid in ionophore-stimulated neutrophils. Esterification of a hydroxylated metabolite into phospholipids, J. Clin. Invest. 64: 1457 (1979).PubMedCrossRefGoogle Scholar
  48. 48.
    R. W. Bonser, M. I. Siegel, S. M. Chung, R. T. McConnell, and P. Cuatrecasas, Esterification of an endogenously synthesized lipoxygenase product into granulocyte cellular lipids, Biochemistry 20: 5297 (1981).PubMedCrossRefGoogle Scholar
  49. 49.
    C. J. Meade, G. A. Turner, and P. E. Bateman, The role of polyphosphoinositides and their metabolic products in A23187-induced release of arachidonic acid from rabbit polymorphonuclear leukocytes, Biochem. J. 238: 425 (1986).PubMedGoogle Scholar
  50. 50.
    H. M. Korchak, L. E. Rutherford, and G. Weissman, Stimulus response coupling in the human neutrophil. Kinetic analysis of changes in calcium permeability. J. Biol. Chem. 259: 4070 (1984).PubMedGoogle Scholar
  51. 51.
    D. Pittet, D. P. Lew, G. W. Mayr, A. Monod, and W. Schlegel, Chemotactic receptor promotion of Ca2+ influx across the plasma membrane of HL-60 cells. A role for cytosolic free calcium elevations and inositol (1, 3, 4, 5)-tetrakisphophate production. J. Biol. Chem. 264: 7251 (1989).PubMedGoogle Scholar
  52. 52.
    F. Alonso, P. M. Henson, and C. C. Leslie, A cytosolic phospholipase in human neutrophils that hydrolyzes arachidonyl-containing phosphatidylcholine, Biochim. Biophys. Acta 878: 273 (1986).PubMedGoogle Scholar
  53. 53.
    B. Samuelsson and C. D. Funk, Enzymes involved in the biosynthesis of Leukotriene B4, J. Biol. Chem. 264: 19469 (1989).PubMedGoogle Scholar
  54. 54.
    P. H. Naccache, R. I. Sha’afi, P. Borgeat, and E. J. Goetzl, Mono-and dihydroxyeicosatetraenoic acids alter calcium homeostasis in rabbit neutrophils. J. Clin. Invest. 67: 1584 (1981).PubMedCrossRefGoogle Scholar
  55. 55.
    D. Piomelli, A. Volterra, N. Dale, S. A. Siegelbaum, E. R. Kandel, J. H. Schwartz, and F. Belardetti, Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplvsia sensory cells, Nature 328: 38 (1987).PubMedCrossRefGoogle Scholar
  56. 56.
    J. F. DiPersio, P. Billing, R. Williams, and J. C. Gasson, Human granulocyte-macrophage colony stimulating factor and other cytokines prime human neutrophils for enhanced arachidonic acid release and leukotriene B4 synthesis, J. Immunol. 140: 4315 (1988).Google Scholar
  57. 57.
    J. Nishihira and J. T. O’Flaherty, Phorbol myristate acetate receptors in human polymorphonuclear neutrophils, J. Immunol. 135: 3439 (1985).PubMedGoogle Scholar
  58. 58.
    M. Wolfson, L. C. McPhail, V. N. Nasrallah, and R. Snyderman, Phorbol myristate acetate mediates redistribution of protein kinase C in human neutrophils: potential role in the activation of the respiratory burst enzyme, J. Immunol. 135: 2057 (1985).PubMedGoogle Scholar
  59. 59.
    M. D. Bazzi and G. L. Nelsestuen, Properties of membrane-inserted protein kinase C, Biochemistry 27: 7589 (1988).PubMedCrossRefGoogle Scholar
  60. 60.
    M. D. Bazzi and G. L. Nelsestuen, Properties of the protein kinase C-phorbol ester interaction, Biochemistry 28: 3577 (1989).PubMedCrossRefGoogle Scholar
  61. 61.
    M. D. Bazzi and G. L. Nelsestuen, Differences in the effects of phorbol esters and diacylglycerols on protein kinase C, Biochemistry 28: 9317 (1989).PubMedCrossRefGoogle Scholar
  62. 62.
    H. Hidaka, M. Inagaki, S. Kawamoto, and Y. Sasaki, Isoquinoline sulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C, J. Biol. Chem. 23: 5036 (1984).Google Scholar
  63. 63.
    E. Wilson, M. C. Olcott, B. M. Bell, A. H. Merrill, and J. D. Lambeth, Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst. J. Biol. Chem. 261: 12616 (1986).PubMedGoogle Scholar
  64. 64.
    A. B. Jefferson and H. Schulman, Sphingosine inhibits calmodulin-dependent enzymes, J. Biol. Chem. 263: 15241 (1988).PubMedGoogle Scholar
  65. 65.
    C. Schneider, M. Zanetti, and D. Romeo, Surface reactive stimuli selectively increase protein phosphorylation in human neutrophils, FEBS Lett. 127: 4 (1981).PubMedCrossRefGoogle Scholar
  66. 66.
    J. A. Badwey, P. G. Heyworth, and M. L. Karnovsky, Phosphorylation of both 47 and 49kDa proteins accompanies superoxide release by neutrophils, Biochem. Biophys. Res. Commun. 158: 1029 (1989).PubMedCrossRefGoogle Scholar
  67. 67.
    J. R. White, C.-H. Huang, J. M. Hill, P. H. Naccache, E. L. Becker, and R. I. Sha’afi, Effect of phorbol 12-myristate 13-acetate and its analogue 4-∝-phorbol-12, 13-didecanoate on protein phosphorylation and lysosomal enzyme release in rabbit neutrophils. J. Biol. Chem. 259: 8605 (1984).PubMedGoogle Scholar
  68. 68.
    I. M. Kramer, R. L. Verhoeven, R. L. van der Bend, R. S. Weening, and D. Roos, Purified protein kinase C phosphorylates a 47-kDa protein in control neutrophil cytoplasts but not in cytoplasts from patients with the autosomal form of chronic granulomatous disease, J. Biol. Chem. 263: 6777 (1988).Google Scholar
  69. 69.
    J. A. Badwey, W. Horn, P. G. Heyworth, J. M. Robinson, and M. L. Karnovsky, Paradoxical effects of retinal in neutrophil stimulation, J. Biol. Chem. 264: 14947 (1989).PubMedGoogle Scholar
  70. 70.
    P. G. Heyworth, M. L. Karnovsky, and J. A. Badwey, Protein phosphorylation associated with synergistic stimulation of neutrophils, J. Biol. Chem. 264: 14935 (1989).PubMedGoogle Scholar
  71. 71.
    J. T. O’Flaherty and J. Nishihira, 5-Hydroxyicosatetraenoate promote Ca2+ and protein kinase C mobilization in neutrophils, Biochem. Biophys. Res. Commun. 148: 575 (1987).PubMedCrossRefGoogle Scholar
  72. 72.
    J. E. Ferrel Jr. and G. S. Martin, Thrombin stimulates the activities of multiple previously unidentified protein kinases in platelets, J. Biol. Chem. 264: 20723 (1989).Google Scholar
  73. 73.
    U. Kikkawa, Y. Takai, Y. Tanaka, R. Miyake, and Y. Nishizuka, Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters, J. Biol. Chem. 258: 11442 (1983).PubMedGoogle Scholar
  74. 74.
    Y. A. Hannun and R. M. Bell, Phorbol ester binding and activation of protein kinase C on triton X-100 mixed micelles containing phosphatidylserine, J. Biol. Chem. 261: 9341 (1986).PubMedGoogle Scholar
  75. 75.
    Y. A. Hannun, C. R. Loomis, and R. M. Bell, Protein kinase C activation in mixed micelles. Mechanistic implications of phospholipid, diacylglycerol, and calcium interdependencies, J. Biol. Chem. 261: 7184 (1986).PubMedGoogle Scholar
  76. 76.
    M. Wolf, P. Cuatrecasas, and N. Sahyoun, Interaction of protein kinase C with membranes is regulated by Ca2+, phorbol esters, and ATP, J. Biol. Chem. 260: 15718 (1985).PubMedGoogle Scholar
  77. 77.
    M. Wolf, H. LeVine III, W. S. May Jr., P. Cuatrecasas, and N. Sahyoun, A model for intracellular translocation of protein kinase C involving synergism between Ca2+ and phorbol esters, Nature 317: 546 (1985).PubMedCrossRefGoogle Scholar
  78. 78.
    W. S. May Jr., N. Sahyoun, M. Wolf, and P. Cuatrecasas, Role of intracellular Ca2+ mobilization in the regulation of protein kinase C-mediated membrane processes, Nature 317: 549 (1985).PubMedCrossRefGoogle Scholar
  79. 79.
    W. A. Phillips, T. Fujiki, M. W. Rossi, H. M. Korchak, and R. B. Johnston, Influence of calcium on the subcellular distribution of protein kinase C in human neutrophils. Extraction conditions determine partitioning of histone-phosphorylating activity and immunoreactivity between cytosol and particulate fractions, J. Biol. Chem. 264: 8361 (1989).PubMedGoogle Scholar

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© Plenum Press, New York 1991

Authors and Affiliations

  • John A. Badwey
    • 1
    • 2
  • Jiabing Ding
    • 1
  • Paul G. Heyworth
    • 3
  • John M. Robinson
    • 4
  1. 1.Department of Cell PhysiologyBoston Biomedical Research InstituteUSA
  2. 2.Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBostonUSA
  3. 3.Department of Molecular and Experimental MedicineResearch Institute of Scripps ClinicLa JollaUSA
  4. 4.Department of Cell Biology, Neurobiology and Anatomy, Program in Molecular, Cellular and Developmental Biology and the Ohio State Biochemistry ProgramThe Ohio State UniversityColumbusUSA

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