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Function and regulation of chemoattractant receptors

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Abstract

Phagocyte migration and activation at sites of inflammation is mediated through chemoattractant receptors that are coupled to G-proteins. Early studies from our laboratory demonstrated G-protein-mediated phospholipase C activation by chemoattractants. Recently, this laboratory developed cellular and animal models to allow biochemical, cell biological and molecular genetic approaches to be used in determining the mechanisms of chemoattractant receptor function, regulation, and cross regulation. These studies provided evidence that chemoattractant receptors activate distinct pathways for chemotaxis and exocytosis and cross-regulate each other's function at multiple levels. A major site of regulation is through phosphorylation of receptors by G-protein-coupled receptor kinases and by protein kinase C. In addition, the activation of phospholipase C by chemoattractants is also regulated, at additional sites distal to receptor phosphorylation. These may include modulation of G-protein activation by regulators of G-protein signaling (RGS) and modification of phospholipase C. Phosphorylation of phospholipase Cβ3 by both protein kinase A and protein kinase C has been demonstrated. The function and regulation of chemoattractant receptors are also being examined in mouse models. In these studies, mice deficient in leukotriene B4 receptors have been generated by targeted gene disruption. These mice displayed reduced neutrophil accumulation in certain inflammation models and sex-related differences in platelet-activating-factor induced anaphylaxis.

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References

  1. Ali H, Haribabu B, Richardson RM, Snyderman R: Mechanisms of inflammation and leukocyte activation. Med Clin North Am 1997;81:1–28.

    Article  PubMed  CAS  Google Scholar 

  2. Uhing RJ, Snyderman R: Chemoattractant stimulus-response coupling. In inflammation: Basic principles and clinical correlates. Gallin JI, Snyderman R (eds.) New York: Raven Press, 1999;607–626.

    Google Scholar 

  3. Baggiolini M, Kernen P, Deranleau DA, Dewald B: Control of motility, exocytosis and the respiratory burst in human neutrophils. Biochem Soc Trans 1991;19: 55–59.

    PubMed  CAS  Google Scholar 

  4. Truett APd, Verghese MW, Dillon SB, Snydennan R: Calcium influx stimulates a second pathway for sustained diacylglycerol production in leukocytes-activated by chemoattractants. Proc Natl Acad Sci USA 1988;85:1549–1553.

    Article  PubMed  CAS  Google Scholar 

  5. Baggiolini M, Dewald B, Moser B: Human Chemokines—an update [Review]. Ann Rev Immunology 1997;15:675–705.

    Article  CAS  Google Scholar 

  6. Murphy PM: Chemokine receptors: structure, function and role in microbial pathogenesis. Cytokine Growth Factor Rev 1996;7: 47–64.

    Article  PubMed  CAS  Google Scholar 

  7. Verghese MW, Smith CD, Snyderman R: Potential role for a guanine nucleotide regulatory protein in chemoattractant receptor mediated polyphosphoinositide metabolism, Ca++ mobilization and cellular responses by leukocytes. Biochem Biophys Res Commun 1985;127:450–457.

    Article  PubMed  CAS  Google Scholar 

  8. Smith CD, Cox CC, Snyderman R: Receptor-coupled activation of phosphoinositide-specific phospholipase C by an N protein. Science 1986;232:97–100.

    Article  PubMed  CAS  Google Scholar 

  9. Verghese MW, Charles L, Jakoi L, Dillon SB, Snyderman R: Role of a guanine nucleotide regulatory protein in the activation of phospholipase C by different chemoattractants. J Immunol 1987;138: 4374–4380.

    PubMed  CAS  Google Scholar 

  10. Haribabu B, Zhelev DV, Pridgen BC, Richardson RM, Ali H, Snyderman R: Chemoattractant receptors activate distinct pathways for chemotaxis and secretion—Role of G-protein usage. J Biol Chem 1999;274:37,087–37,092.

    Article  CAS  Google Scholar 

  11. Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D: Roles of PLC-beta2 and-beta3 and P13K gamma inchemoattractant-mediated signal transduction [see comments]. Science 2000;287:1046–1049.

    Article  PubMed  CAS  Google Scholar 

  12. Alteraifi AM, Zhelev DV: Transient increase of free cytosolic calcium during neutrophil motility responses. J Cell Sci 1997;110: 1967–1977.

    PubMed  CAS  Google Scholar 

  13. Zhelev DV, Alteraifi AM, Hochmuth RM: F-actin network formation in tethers and in pseudopods stimulated by chemoattractant. Cell Motil Cytoskeleton 1996;35: 331–344.

    Article  PubMed  CAS  Google Scholar 

  14. Arai H, Monteclaro FS, Tsou CL, Franci C, Charo IF: Dissociation of chemotaxis from agonist-induced receptor internalization in a lymphocyte cell line, transfected with Cer2b—evidence that directed migration does not require rapid modulation of signaling at the receptor level. J Biol Chem 1997; 272:25,037–25,042.

    Article  CAS  Google Scholar 

  15. Neptune ER, Boume HR: Receptors Induce Chemotaxis By Releasing the Beta-Gamma Subunit of G(I), Not By Activating G (Q) or G(S). Proc Natl Acad Sci USA 1997;94:14,489–14,494.

    Article  CAS  Google Scholar 

  16. Neptune ER, Iiri T, Bourne HR: Galphai is not required for chemotax is mediated by Gi-coupled receptors. J Biol Chem 1999;274: 2824–2828.

    Article  PubMed  CAS  Google Scholar 

  17. Hartwig JH, Bokoch GM, Carpenter CL, et al.: Thrombin receptor ligation and activated, Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets. Cell 1995;82:643–653.

    Article  PubMed  CAS  Google Scholar 

  18. Knall C, Worthen GS, Johnson GL: Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proc Natl Acad Sci USA 1997;94:3052–3057.

    Article  PubMed  CAS  Google Scholar 

  19. Keely PJ, Westwick JK, Whitehead IP, Der CJ, Parise LV: Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 1997;390:632–636.

    Article  PubMed  CAS  Google Scholar 

  20. Tapon N, Hall A: Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton. Curr Opin Cell Biol 1997;9:86–92.

    Article  PubMed  CAS  Google Scholar 

  21. Zigmond SH, Joyce M, Borleis K, Bokoch GM, Devreotes PN: Regulation of actin polymerization in cell-free systems by GTPgamma S and Cdc42. J Cell Biol 1997;138: 363–374.

    Article  PubMed  CAS  Google Scholar 

  22. Hausdorff WP, Caron MG, Lefkowitz RJ: Turning off the signal: desensitization of beta-adrenergic receptor function [published erratum appears in FASEB J 1990; 4(12):3049]. Faseb J 1990;4: 2881–2889.

    PubMed  CAS  Google Scholar 

  23. Haribabu B, Snyderman R: Identification of additional members of human G-protein-coupled receptor kinase multigene family. Proc Natl Acad Sci USA 1993;90: 9398–9402.

    Article  PubMed  CAS  Google Scholar 

  24. Ferguson SS, Barak LS, Zhang J, Caron MG: G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins. Can J Physiol Pharmacol 1996;74:1095–1110.

    Article  PubMed  CAS  Google Scholar 

  25. Didsbury JR, Uhing RJ, Tomhave E, Gerard C, Gerard N, Snyderman R: Receptor class desensitization of leukocyte chemoattractant receptors. Proc Natl Acad Sci USA 1991;88:11,564–11,568.

    Article  CAS  Google Scholar 

  26. Ali H, Richardson RM, Haribabu B, Snyderman R: Chemoattractant receptor cross-desensitization [Review]. J Biol Chem 1999;274: 6027–6030.

    Article  PubMed  CAS  Google Scholar 

  27. Richardson R, Snyderman R, Haribabu B: Chemokine receptor expression and regulatory mechanisms. In Chemokine receptors, human genetics and AIDS: in sights into pathogenesis and new therapeutic options. O'Brien T (ed.) New York: Marcel Decker (in press).

  28. Ali H, Richardson RM, Tomhave ED, Disbury JR, Snyderman R: Differences in phosphorylation of formylpeptide and C5a chemoattractant receptors correlate with differences in desensitization. J Biol Chem 1993;268:24,247–24,254.

    CAS  Google Scholar 

  29. Ali H, Richardson RM, Tomhave ED, DuBose RA, Haribabu B, Snyderman R: Regulation of stably transfected platelet activating factor receptor in RBL-2H3 cells. Role of multiple G proteins and receptor phosphorylation. J Biol Chem 1994;269:24,557–24,563.

    CAS  Google Scholar 

  30. Haribabu B, Richardson RM, Fisher I, et al.: Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and intemalization. J Biol Chem 1997;272: 28,726–28,731.

    CAS  Google Scholar 

  31. Richardson RM, Haribabu B, Ali H, Snyderman R: Cross-desensitization among receptors for platelet activating factor and peptide chemoattractants. Evidence for independent regulatory path-ways. J Biol Chem 1996;271: 28,717–28,724.

    CAS  Google Scholar 

  32. Richardson RM, Ali H, Pridgen BC, Haribabu B, Snyderman R: Multiple signaling pathways of human interleukin-8 receptor a—independent regulation by phosphorylation. J Biol Chem 1998; 273:10,690–10,695.

    CAS  Google Scholar 

  33. Richardson RM, Pridgen BC, Haribabu B, Ali H, Snyderman R: Differential cross-regulation of the human chemokine receptors Cxcr1 and Cxcr2—evidence for time-dependent signal genetation. J Biol Chem 1998;273:23,830–23,836.

    CAS  Google Scholar 

  34. Takano T, Honda Z, Sakanaka C, et al.: Role of cytoplasmic tail phosphorylation sites of platelet-activating factor receptor in agonist-induced desensitization. J Biol Chem 1994;269:22,453–22,458.

    CAS  Google Scholar 

  35. Mueller SG, Schraw WP, Richmond A: Activation of protein kinase C enhances the phosphory lation of the type B interleukin-8 receptor and stimulates its degradation in non-hematopoietic cells. J Biol Chem 1995;270:10,439–10,448.

    Article  CAS  Google Scholar 

  36. Richardson RM, Pridgen, BC, Haribabu B, Snyderman R: Regulation of the human chemokine receptor CCR1: cross regulation by CXCR1 and CXCR2. J Biol Chem 2000;275:9201–9208.

    Article  PubMed  CAS  Google Scholar 

  37. Richardson RM, Ali H, Tomhave ED, Haribabu B, Snyderman R: Cross-densitization of chemoattractant receptors occurs at multiple levels. Evidence for a role for inhibition of phospholipase C activity. J Biol Chem 1995;270:27,829–27,833.

    Article  CAS  Google Scholar 

  38. Ali H, Fisher I, Haribabu B, Richardson RM, Snyderman R: Role of phospholipase C B 3 phosphorylation in the desensitization of cellular responses to platelet activating factor. J Biol Chem 1997;272:11,706–11,709.

    CAS  Google Scholar 

  39. Liu M, Simon MI: Regulation by cAMP-dependent protein kinase of a G-protein-mediated phospholipase C. Nature 1996;382:83–87.

    Article  PubMed  CAS  Google Scholar 

  40. Ali H, Sozzani S, Fisher I, et al.: Differential regulation of fomyl peptide and platelet-activating factor receptors—role of phospholipase C-beta(3) phosphorylation by protein kinase a. J Biol Chem 1998;273:11,012–11,016.

    CAS  Google Scholar 

  41. Flitz T, Cunningham ML, Staining KJ, Paterson A, Harden TK: Phosphorylation by protein kinase C decreases catalytic activity of avian phospholipase c-beta. Biochem J 1999;338:257–264.

    Article  Google Scholar 

  42. Dohlman HG, Thorner J: RGS proteins and signaling by heterotrimeric G proteins. J Biol Chem 1997;272:3871–3874.

    Article  PubMed  CAS  Google Scholar 

  43. Bowman EP, Campbell JJ, Druey KM, Scheschonka A, Kehrl JH, Butcher EC: Regulation of chemotactic and proadhesive responses to chemoattractant receptors by Rgs (regulator of G-protein signaling) family members. J Biol Chem 1998;273:28,040–28,048.

    Article  CAS  Google Scholar 

  44. Rosenkranz AR, Mayadas TN: Leukocyte-endothelial cell interactions—lessons from knockout mice [Review]. Exper Nephorology 1999;7:125–136.

    Article  CAS  Google Scholar 

  45. Gao JL, Lee EJ, Murphy PM: Impairedantibacterial host defense in mice lacking the N-formyl-peptide receptor. J Exp Med 1999;189:657–662.

    Article  PubMed  CAS  Google Scholar 

  46. Hopken UE, Lu B, Gerard NP, Gerard C: The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 1996; 383:86–89.

    Article  PubMed  CAS  Google Scholar 

  47. Cacalano G, Lee J, Kikly K, et al.: Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog [see comments] [published erratum appears in Science 1995:270 (5235): 365]. Science 1994;265:682–684.

    Article  PubMed  CAS  Google Scholar 

  48. Gao JL, Wynn TA, Chang Y, et al.: Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. J Exp Med 1997;185:1959–1968.

    Article  PubMed  CAS  Google Scholar 

  49. Boring L, Gosling J, Cleary M, Charo IF: Decreased lesion formation in Ccr2(−/−) mice reveals a role for chemokines in the initiation of a the rosclerosis. Nature 1998;394:894–897.

    Article  PubMed  CAS  Google Scholar 

  50. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M: A putative chemokine receptor, Blrl, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 1996;87:1037–1047.

    Article  PubMed  CAS  Google Scholar 

  51. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, Lipp M: CCR7 coordirates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999;99:23–33.

    Article  PubMed  CAS  Google Scholar 

  52. Tachibana K, Hirota S, Iizasa H, et al.: The chemokine receptor CXCR4 is essential for vascularization of the gastroin testinaltract [see comments]. Nature 1998;393:591–594.

    Article  PubMed  CAS  Google Scholar 

  53. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR: Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development [see comments]. Nature 1998;393:595–599.

    Article  PubMed  CAS  Google Scholar 

  54. Haribabu B, Verghese MW, Steeber DA, Sellars DD, Bock CB, Snydeman R: Targeled disruption of the leukotriene B-4 receptor in mice reveals its role in inflammation and platelet-activating factor-induced anaphylaxis. J Exper Med 2000;192:433–438.

    Article  CAS  Google Scholar 

  55. Tager AM, Dufour JH, Goodarzi K, Bercury SD, von Andrian UH, Luster AD: BLTR mediates leukotriene B-4-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis. J Exper Med 2000;192:439–446.

    Article  CAS  Google Scholar 

  56. Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T: A second leukotriene B-4 receptor, BLT2: A new therapeutic target in inflammation and immunological disorders. J Exper Med 2000;192:421–431.

    Article  CAS  Google Scholar 

  57. Griffiths RJ, Smith MA, Roach ML, et al.: Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice. J Exp Med 1997;185:1123–1129.

    Article  PubMed  CAS  Google Scholar 

  58. Kuwabara K, Yasui K, Jyoyama H, Maruyama T, Fleisch JH, Hori Y: Effects of the second-generation leukotriene B-4 receptor antagonist, LY29311 1Na, on leukocyte infiltration and collagen-induced arthritis in mice. Eur J Pharmacology 2000;402:275–285.

    Article  CAS  Google Scholar 

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Author notes

  1. Bodduluri Haribabu

    Present address: Department of Immunology, Duke University Medical Center, Box 3701, 27710, Durham, NC

Authors and Affiliations

  1. Department of Medicine, Duke University Medical Center, Box 3701, 27710, Durham, NC

    Bodduluri Haribabu, Ricardo M. Richardson, Margrith W. Verghese, Alastair J. Barr & Ralph Snyderman

  2. Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC

    Doncho V. Zhelev

  3. Department of Pathology, University of Louisville Medical Center, Louisville, KY

    Ralph Snyderman

Authors
  1. Bodduluri Haribabu
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  2. Ricardo M. Richardson
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  3. Margrith W. Verghese
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  4. Alastair J. Barr
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  5. Doncho V. Zhelev
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  6. Ralph Snyderman
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Correspondence to Ralph Snyderman.

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Haribabu, B., Richardson, R.M., Verghese, M.W. et al. Function and regulation of chemoattractant receptors. Immunol Res 22, 271–279 (2000). https://doi.org/10.1385/IR:22:2-3:271

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