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Table of Contents
Vol. 34, No. 4-5, 2005
Issue release date: May 2006
Section title: Paper
Pathophysiol Haemos Thromb 2005;34:221–227
(DOI:10.1159/000092428)

Antihemostatic Molecules from Saliva of Blood-Feeding Arthropods

Champagne D.E.
Department of Entomology, and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Ga., USA
email Corresponding Author

Abstract

The ability to feed on vertebrate blood has evolved many times in various arthropod clades. Each time this trait evolves, novel solutions to the problem posed by vertebrate hemostasis are generated. Consequently, saliva of blood-feeding arthropods has proven to be a rich source of antihemostatic molecules. Vasodilators include nitrophorins (nitric oxide storage and transport heme proteins), a variety of peptides that mimic endogenous vasodilatory neuropeptides, and proteins that catabolize or sequester endogenous vasoconstrictors. A variety of platelet aggregation inhibitors antagonize platelet responses to wound-generated signals, including ADP, thrombin, and collagen. Anticoagulants disrupt elements of both the intrinsic and extrinsic pathways. Molecular approaches (termed ‘sialomics’) to characterize the full inventory of mRNAs transcribed in salivary glands have revealed a surprising level of complexity within a single species. Multiple salivary proteins may be directed against each component of hemostasis, resulting in both redundancy and in some cases cooperative interactions between antihemostatic proteins, as in the case of the Rhodnius prolixus apyrase (which hydrolyzes ADP) and Rhodnius platelet aggregation inhibitor 1 (which sequesters ADP). The complexity and redundancy of saliva ensures an efficient blood meal for the arthropod, but it also provides a diverse array of novel antihemostatic molecules for the pharmacologist.

© 2005 S. Karger AG, Basel


  

Key Words

  • Vasodilators
  • Anticoagulants
  • Platelet aggregation inhibitors
  • Saliva
  • Blood-feeding
  • Rhodnius prolixus
  • Nitrophorin

References

  1. Ribeiro JM: Blood feeding arthropods: live syringes or invertebrate pharmacologists? Infect Agents and Dis 1995;4:143–152.
  2. Champagne DE: Antihemostatic strategies of blood-feeding arthropods. Curr Drug Targets 2004;4:375–396.
  3. Ribeiro JM, Marinotti O, Gonzales R: A salivary vasodilator in the blood-sucking bug, Rhodnius prolixus. Br J Pharmacol 1990;101:932–936.
  4. Ribeiro JM, Hazzard JM, Nussenzveig RH, Champagne DE, Walker FA: Reversible binding of nitric oxide by a salivary heme protein from a bloodsucking insect. Science 1993:260:539–541.
  5. Andersen JF, Champagne DE, Weichsel A, Ribeiro JM, Balfour CA, Dress V, Montfort WR: Nitric oxide binding and crystallization of recombinant nitrophorin I, a nitric oxide transport protein from the blood-sucking bug Rhodnius prolixus. Biochemistry 1997;36:4423–4428.
  6. Champagne DE, Nussenzveig RH, Ribeiro JM: Purification, partial characterization, and cloning of nitric oxide-carrying heme proteins (nitrophorins) from salivary glands of the blood-sucking insect Rhodnius prolixus. J Biol Chem 1995;270:8691–8695.
  7. Weichsel A, Andersen JF, Champagne DE, Walker FA, Montfort WR: Crystal structures of a nitric oxide transport protein from a blood-sucking insect. Nat Struct Biol 1998;5:304–309.
  8. Andersen JF, Weichsel A, Balfour CA, Champagne DE, Montfort WR: The crystal structure of nitrophorin 4 at 1.5 A resolution: transport of nitric oxide by a lipocalin-based heme protein. Structure 1998;6:1315–1327.
  9. Andersen JF, Montfort WR: The crystal structure of nitrophorin 2. A trifunctional antihemostatic protein from the saliva of Rhodnius prolixus. J Biol Chem 2000;275:30496–30503.
  10. Weichsel A, Andersen JF, Roberts SA, Montfort WR: Nitric oxide binding to nitrophorin 4 induces complete distal pocket burial. Nat Struct Biol 2000;7:551–554.
  11. Andersen JF, Ding XD, Balfour C, Shokhireva TK, Champagne DE, Walker FA, Montfort WR: Kinetics and equilibria in ligand binding by nitrophorins 1–4: evidence for stabilization of a nitric oxide-ferriheme complex through a ligand induced conformational trap. Biochemistry 2000;39:10118–10131.
  12. Yuda M, Higuchi K, Sun J, Kureishi Y, Ito M, Chinzei Y: Expression, reconstitution and characterization of prolixin-S as a vasodilator: a salivary gland nitric-oxide-binding hemoprotein of Rhodnius prolixus. Eur J Biochem 1997;249:337–342.
  13. Ribeiro JM: The antiserotonin and antihistamine activities of salivary secretion of Rhodnius prolixus. J Insect Physiol 1982;28:69–75.
  14. Ribeiro JM, Walker FA: High affinity histamine-binding and antihistaminic activity of the salivary nitric oxide-carrying heme protein (nitrophorin) of Rhodnius prolixus. J Exp Med 1994;180:2251–2257.
  15. Valenzuela JG, Ribeiro JM: Purification and cloning of the salivary nitrophorin from the hemipteran Cimex lectularius. J Exp Biol 1998;201:2659–2664.
  16. Weichsel A, Maes EM, Andersen JF, Valenzuela JG, Shokhireva TKH, Walker FA, Montfort WR: Heme-assisted S-nitrosation of a proximal thiolate in a nitric oxide transport protein. Proc Natl Acad Sci USA 2005;102:594–599.
  17. Ribeiro JM: Characterization of a vasodilator from the salivary glands of the yellow fever mosquito Aedes aegypti. J Exp Biol 1992;165:61–71.
  18. Champagne DE, Ribeiro JM: Sialokinin I and II: vasodilatory tachykinins from the yellow fever mosquito Aedes aegypti. Proc Natl Acad Sci USA 1994;91:138–142.
  19. Beerntsen BT, Champagne DE, Coleman JL, Campos YA, James AA: Characterization of the Sialokinin I gene encoding the salivary vasodilator of the yellow fever mosquito, Aedes aegypti. Insect Mol Biol 1999;8:459–467.
  20. Lerner EA, Ribeiro JM, Nelson RJ, Lerner MR: Isolation of maxadilan, a potent vasodilatory peptide from the salivary glands of the sand fly Lutzomyia longipalpis. J Biol Chem 1991:266:11234–11236.
  21. Lerner EA, Shoemaker CB: Maxadilan. Cloning and functional expression of the gene encoding this potent vasodilator peptide. J Biol Chem 1992;267:1062–1066.
  22. Moro O, Lerner EA: Maxadilan, the vasodilator from sand flies, is a specific pituitary adenylate cyclase activating peptide type I receptor agonist. J Biol Chem 1997;272:966–970.
  23. Cupp MS, Ribeiro JM, Champagne DE, Cupp EW: Analyses of cDNA and recombinant protein for a potent vasoactive protein in saliva of a blood-feeding black fly, Simulium vittatum. J Exp Biol 1998;201:1553–1561.
  24. Ribeiro JM: NAD(P)H-dependent production of oxygen reactive species by the salivary glands of the mosquito Anopheles albimanus. Insect Biochem Mol Biol 1996;26:715–720.
  25. Ribeiro JM, Valenzuela JG: Purification and cloning of the salivary peroxidase/catechol oxidase of the mosquito Anopheles albimanus. J Exp Biol 1999;202:809–816.
  26. Ribeiro JM. Katz O, Pannell LK, Waitumbi J, Warburg A: Salivary glands of the sand fly Phlebotomus papatasi contain pharmacological amounts of adenosine and 5′-AMP. J Exp Biol 1999;202:1551–1559.
  27. Ribeiro JM, Schneider M, Isaias T, Jurberg J, Galvao C, Guimaraes JA: Role of salivary antihemostatic components in blood feeding by triatomine bugs (Heteroptera). J Med Entomol 1998;35:599–610.
  28. Bowman AS, Dillwith JW, Sauer JR: Tick salivary prostaglandins: presence, origin, and significance. Parasitol Today 1996;12:388–395.
  29. Astigarraga A, Oleaga-Perez A, Perez-Sanchez R, Baranda JA, Encinas-Grandes A: Host immune response evasion strategies in Ornithodoros erraticus and O. moubata and their relationship to the development of an antiargasid vaccine. Parasite Immunol 1997;19:401–410.
  30. Champagne DE, Smartt CT, Ribeiro JM, James AA: The salivary gland-specific apyrase of the mosquito Aedes aegypti is a member of the 5′-nucleotidase family. Proc Natl Acad Sci USA 1995;92:694–698.
  31. Arca B, Lombardo F, de Lara Capurro M, della Torre A, Dimopoulos G, James AA, Coluzzi M: Trapping cDNAs encoding secreted proteins from the salivary glands of the malaria vector Anopheles gambiae. Proc Natl Acad Sci USA 1999;96:1516–1521.
  32. Faudry E, Lozzi SP, Santana JM, D’Souza-Ault M, Kieffer S, Felix CR, Ricart CA, Sousa MV, Vernet T, Teixeira AR: Triatoma infestans apyrases belong to the 5′-nucleotidase family. J Biol Chem 2004;279:19607–19613.
  33. Valenzuela JG, Charlab R, Galperin MY, Ribeiro JM: Purification, cloning, and expression of an apyrase from the bed bug Cimex lectularius. A new type of nucleotide-binding enzyme. J Biol Chem 1998;273:30583–30590.
  34. Valenzuela JG, Belkaid Y, Rowton E, Ribeiro JMC: The salivary apyrase of the blood-sucking sand fly Phlebotomus papatasi belongs to the novel Cimex family of apyrases. J Exp Biol 2001;204:229–237.
  35. Valenzuela JG, Garfield M, Rowton ED, Pham VM: Identification of the most abundant secreted proteins from the salivary glands of the sand fly Lutzomyia longipalpis, vector of Leishmania chagasi. J Exp Biol 200;207:3717–3729.
  36. Champagne DE, Valenzuela JG: Pharmacology of haematophagous arthropod saliva; in Wikel SK (ed): The Immunology of Host-Ectiparasitic Arthropod Relationships. Wallingford, CAB International, 1996.
  37. Francischetti IM, Ribeiro JM, Champagne D, Andersen J: Purification, cloning, expression, and mechanism of action of a novel platelet aggregation inhibitor from the salivary gland of the blood-sucking bug, Rhodnius prolixus. J Biol Chem 2000;275:12639–12650.
  38. Francischetti IM, Andersen JF, Ribeiro JM: Biochemical and functional characterization of recombinant Rhodnius prolixus platelet aggregation inhibitor 1 as a novel lipocalin with high affinity for adenosine diphosphate and other adenine nucleotides. Biochemistry 2002;41:3810–3818.
  39. Andersen JF, Francischetti IM, Valenzuela JG, Schuck P, Ribeiro JM: Inhibition of hemostasis by a high affinity biogenic amine-binding protein from the saliva of a blood-feeding insect. J Biol Chem 2003;278:4611–4617.
  40. Sangamnatdej S, Paesen GC, Slovak M, Nuttall PA: A high affinity serotonin- and histamine-binding lipocalin from tick saliva. Insect Mol Biol 2002;11:79–86.
  41. Stark KR, James AA: Salivary gland anticoagulants in culicine and anopheline mosquitoes (Diptera: Culicidae). J Med Entomol 1996;33:645–650.
  42. Stark KR, James AA: Isolation and characterization of the gene encoding a novel factor Xa-directed anticoagulant from the yellow fever mosquito, Aedes aegypti. J Biol Chem 1998;273:20802–20809.
  43. Valenzuela JG, Francischetti IM, Ribeiro JM: Purification, cloning, and synthesis of a novel salivary anti-thrombin from the mosquito Anopheles albimanus. Biochemistry 1999;38:11209–11215.
  44. Francischetti IM, Valenzuela JG, Ribeiro JM: Anophelin: kinetics and mechanism of thrombin inhibition. Biochemistry 1999;38:16678–16685.
  45. Hellmann K, Hawkins RI: Prolixins-S and prolixin-G; two anticoagulants from Rhodnius prolixus Stal. Nature 1965;207:265–267.
  46. Ribeiro JM, Schneider M, Guimaraes JA: Purification and characterization of prolixin S (nitrophorin 2), the salivary anticoagulant of the blood-sucking bug Rhodnius prolixus. Biochem J 1995;308:243–249.
  47. Sun J, Yamaguchi M, Yuda M, Miura K, Takeya H, Hirai M, Matsuoka H, Ando K, Watanabe T, Suzuki K, Chinzei Y: Purification, characterization and cDNA cloning of a novel anticoagulant of the intrinsic pathway, (prolixin-S) from salivary glands of the blood sucking bug, Rhodnius prolixus. Thromb Haemost 1996;75:573–577.
  48. Zhang Y, Ribeiro JM, Guimaraes JA, Walsh PN: Nitrophorin-2: a novel mixed-type reversible specific inhibitor of the intrinsic factor-X activating complex. Biochemistry 1998;37:10681–10690.
  49. Isawa H, Yuda M, Yoneda K, Chinzei Y: The insect salivary protein, prolixin-S, inhibits factor IXa generation and Xase complex formation in the blood coagulation pathway. J Biol Chem 2000;275:6636–6641.
  50. Gudderra NP, Ribeiro JM, Andersen JF: Structural determinants of factor IX(a) binding in nitrophorin 2, a lipocalin inhibitor of the intrinsic coagulation pathway. J Biol Chem 2005;280:25022–25028.
  51. Andersen JF, Gudderra NP, Francischetti IM, Valenzuela JG, Ribeiro JM: Recognition of anionic phospholipid membranes by an antihemostatic protein from a blood-feeding insect. Biochemistry 2004;43:6987–6994.
  52. Ribeiro JM, Andersen J, Silva-Neto MA, Pham VM, Garfield MK, Valenzuela JG: Exploring the sialome of the blood-sucking bug Rhodnius prolixus. Insect Biochem Mol Biol 2004;34:61–79.
  53. Noeske-Jungblut C, Haendler B, Donner P, Alagon A, Possani L, Schleuning WD: Triabin, a highly potent exosite inhibitor of thrombin. J Biol Chem 1995;270:28629–28634.
  54. Noeske-Jungblut C, Kratzschmar J, Haendler B, Alagon A, Possani L, Verhallen P, Donner P, Schleuning WD: An inhibitor of collagen-induced platelet aggregation from the saliva of Triatoma pallidipennis. J Biol Chem 1994;269:5050–5053.
  55. Charlab R, Valenzuela JG, Rowton ED, Ribeiro JMC: Toward an understanding of the biochemical and pharmacological complexity of the saliva of a hematophagous sand fly Lutziomyia longipalpus. Proc Natl Acad Sci USA 1999;9:15155–15160.

    External Resources

  56. Francischetti IM, Valenzuela JG, Pham VM, Garfield MK, Ribeiro JM: Toward a catalog for the transcripts and proteins (sialome) from the salivary gland of the malaria vector Anopheles gambiae. J Exp Biol 2002;205:2429–2451.
  57. Ribeiro JM, Charlab R, Pham VM, Garfield M, Valenzuela JG: An insight into the salivary transcriptome and proteome of the adult female mosquito Culex pipiens quinquefasciatus. Insect Biochem Mol Biol 2004;34:543–563.
  58. Valenzuela JG, Francischetti IM, Pham VM, Garfield MK, Mather TN, Ribeiro JM: Exploring the sialome of the tick Ixodes scapularis. J Exp Biol 2002;205:2843–2864.
  59. Valenzuela JG, Pham VM, Garfield MK, Francischetti IM, Ribeiro JM: Toward a description of the sialome of the adult female mosquito Aedes aegypti. Insect Biochem Mol Biol 2002;32:1101–1122.
  60. Valenzuela JG, Francischetti IM, Pham VM, Garfield MK, Ribeiro JM: Exploring the salivary gland transcriptome and proteome of the Anopheles stephensi mosquito. Insect Biochem Mol Biol 2003;33:717–732.

  

Author Contacts

Donald E. Champagne
Department of Entomology
Center for Tropical and Emerging Global Diseases, University of Georgia
Athens, GA 30602 (USA)
Tel./Fax +1 706 542 2342, E-Mail dchampagne@bugs.ent.uga.edu

  

Article Information

Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 60

  

Publication Details

Pathophysiology of Haemostasis and Thrombosis

Vol. 34, No. 4-5, Year 2005 (Cover Date: May 2006)

Journal Editor: Rosing, J. (Maastricht)
ISSN: 1424–8832 (print), 1424–8840 (Online)

For additional information: http://www.karger.com/PHT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The ability to feed on vertebrate blood has evolved many times in various arthropod clades. Each time this trait evolves, novel solutions to the problem posed by vertebrate hemostasis are generated. Consequently, saliva of blood-feeding arthropods has proven to be a rich source of antihemostatic molecules. Vasodilators include nitrophorins (nitric oxide storage and transport heme proteins), a variety of peptides that mimic endogenous vasodilatory neuropeptides, and proteins that catabolize or sequester endogenous vasoconstrictors. A variety of platelet aggregation inhibitors antagonize platelet responses to wound-generated signals, including ADP, thrombin, and collagen. Anticoagulants disrupt elements of both the intrinsic and extrinsic pathways. Molecular approaches (termed ‘sialomics’) to characterize the full inventory of mRNAs transcribed in salivary glands have revealed a surprising level of complexity within a single species. Multiple salivary proteins may be directed against each component of hemostasis, resulting in both redundancy and in some cases cooperative interactions between antihemostatic proteins, as in the case of the Rhodnius prolixus apyrase (which hydrolyzes ADP) and Rhodnius platelet aggregation inhibitor 1 (which sequesters ADP). The complexity and redundancy of saliva ensures an efficient blood meal for the arthropod, but it also provides a diverse array of novel antihemostatic molecules for the pharmacologist.

© 2005 S. Karger AG, Basel


  

Author Contacts

Donald E. Champagne
Department of Entomology
Center for Tropical and Emerging Global Diseases, University of Georgia
Athens, GA 30602 (USA)
Tel./Fax +1 706 542 2342, E-Mail dchampagne@bugs.ent.uga.edu

  

Article Information

Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 60

  

Publication Details

Pathophysiology of Haemostasis and Thrombosis

Vol. 34, No. 4-5, Year 2005 (Cover Date: May 2006)

Journal Editor: Rosing, J. (Maastricht)
ISSN: 1424–8832 (print), 1424–8840 (Online)

For additional information: http://www.karger.com/PHT


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 5/19/2006
Issue release date: May 2006

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 1424-8832 (Print)
eISSN: 1424-8840 (Online)

For additional information: http://www.karger.com/PHT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Ribeiro JM: Blood feeding arthropods: live syringes or invertebrate pharmacologists? Infect Agents and Dis 1995;4:143–152.
  2. Champagne DE: Antihemostatic strategies of blood-feeding arthropods. Curr Drug Targets 2004;4:375–396.
  3. Ribeiro JM, Marinotti O, Gonzales R: A salivary vasodilator in the blood-sucking bug, Rhodnius prolixus. Br J Pharmacol 1990;101:932–936.
  4. Ribeiro JM, Hazzard JM, Nussenzveig RH, Champagne DE, Walker FA: Reversible binding of nitric oxide by a salivary heme protein from a bloodsucking insect. Science 1993:260:539–541.
  5. Andersen JF, Champagne DE, Weichsel A, Ribeiro JM, Balfour CA, Dress V, Montfort WR: Nitric oxide binding and crystallization of recombinant nitrophorin I, a nitric oxide transport protein from the blood-sucking bug Rhodnius prolixus. Biochemistry 1997;36:4423–4428.
  6. Champagne DE, Nussenzveig RH, Ribeiro JM: Purification, partial characterization, and cloning of nitric oxide-carrying heme proteins (nitrophorins) from salivary glands of the blood-sucking insect Rhodnius prolixus. J Biol Chem 1995;270:8691–8695.
  7. Weichsel A, Andersen JF, Champagne DE, Walker FA, Montfort WR: Crystal structures of a nitric oxide transport protein from a blood-sucking insect. Nat Struct Biol 1998;5:304–309.
  8. Andersen JF, Weichsel A, Balfour CA, Champagne DE, Montfort WR: The crystal structure of nitrophorin 4 at 1.5 A resolution: transport of nitric oxide by a lipocalin-based heme protein. Structure 1998;6:1315–1327.
  9. Andersen JF, Montfort WR: The crystal structure of nitrophorin 2. A trifunctional antihemostatic protein from the saliva of Rhodnius prolixus. J Biol Chem 2000;275:30496–30503.
  10. Weichsel A, Andersen JF, Roberts SA, Montfort WR: Nitric oxide binding to nitrophorin 4 induces complete distal pocket burial. Nat Struct Biol 2000;7:551–554.
  11. Andersen JF, Ding XD, Balfour C, Shokhireva TK, Champagne DE, Walker FA, Montfort WR: Kinetics and equilibria in ligand binding by nitrophorins 1–4: evidence for stabilization of a nitric oxide-ferriheme complex through a ligand induced conformational trap. Biochemistry 2000;39:10118–10131.
  12. Yuda M, Higuchi K, Sun J, Kureishi Y, Ito M, Chinzei Y: Expression, reconstitution and characterization of prolixin-S as a vasodilator: a salivary gland nitric-oxide-binding hemoprotein of Rhodnius prolixus. Eur J Biochem 1997;249:337–342.
  13. Ribeiro JM: The antiserotonin and antihistamine activities of salivary secretion of Rhodnius prolixus. J Insect Physiol 1982;28:69–75.
  14. Ribeiro JM, Walker FA: High affinity histamine-binding and antihistaminic activity of the salivary nitric oxide-carrying heme protein (nitrophorin) of Rhodnius prolixus. J Exp Med 1994;180:2251–2257.
  15. Valenzuela JG, Ribeiro JM: Purification and cloning of the salivary nitrophorin from the hemipteran Cimex lectularius. J Exp Biol 1998;201:2659–2664.
  16. Weichsel A, Maes EM, Andersen JF, Valenzuela JG, Shokhireva TKH, Walker FA, Montfort WR: Heme-assisted S-nitrosation of a proximal thiolate in a nitric oxide transport protein. Proc Natl Acad Sci USA 2005;102:594–599.
  17. Ribeiro JM: Characterization of a vasodilator from the salivary glands of the yellow fever mosquito Aedes aegypti. J Exp Biol 1992;165:61–71.
  18. Champagne DE, Ribeiro JM: Sialokinin I and II: vasodilatory tachykinins from the yellow fever mosquito Aedes aegypti. Proc Natl Acad Sci USA 1994;91:138–142.
  19. Beerntsen BT, Champagne DE, Coleman JL, Campos YA, James AA: Characterization of the Sialokinin I gene encoding the salivary vasodilator of the yellow fever mosquito, Aedes aegypti. Insect Mol Biol 1999;8:459–467.
  20. Lerner EA, Ribeiro JM, Nelson RJ, Lerner MR: Isolation of maxadilan, a potent vasodilatory peptide from the salivary glands of the sand fly Lutzomyia longipalpis. J Biol Chem 1991:266:11234–11236.
  21. Lerner EA, Shoemaker CB: Maxadilan. Cloning and functional expression of the gene encoding this potent vasodilator peptide. J Biol Chem 1992;267:1062–1066.
  22. Moro O, Lerner EA: Maxadilan, the vasodilator from sand flies, is a specific pituitary adenylate cyclase activating peptide type I receptor agonist. J Biol Chem 1997;272:966–970.
  23. Cupp MS, Ribeiro JM, Champagne DE, Cupp EW: Analyses of cDNA and recombinant protein for a potent vasoactive protein in saliva of a blood-feeding black fly, Simulium vittatum. J Exp Biol 1998;201:1553–1561.
  24. Ribeiro JM: NAD(P)H-dependent production of oxygen reactive species by the salivary glands of the mosquito Anopheles albimanus. Insect Biochem Mol Biol 1996;26:715–720.
  25. Ribeiro JM, Valenzuela JG: Purification and cloning of the salivary peroxidase/catechol oxidase of the mosquito Anopheles albimanus. J Exp Biol 1999;202:809–816.
  26. Ribeiro JM. Katz O, Pannell LK, Waitumbi J, Warburg A: Salivary glands of the sand fly Phlebotomus papatasi contain pharmacological amounts of adenosine and 5′-AMP. J Exp Biol 1999;202:1551–1559.
  27. Ribeiro JM, Schneider M, Isaias T, Jurberg J, Galvao C, Guimaraes JA: Role of salivary antihemostatic components in blood feeding by triatomine bugs (Heteroptera). J Med Entomol 1998;35:599–610.
  28. Bowman AS, Dillwith JW, Sauer JR: Tick salivary prostaglandins: presence, origin, and significance. Parasitol Today 1996;12:388–395.
  29. Astigarraga A, Oleaga-Perez A, Perez-Sanchez R, Baranda JA, Encinas-Grandes A: Host immune response evasion strategies in Ornithodoros erraticus and O. moubata and their relationship to the development of an antiargasid vaccine. Parasite Immunol 1997;19:401–410.
  30. Champagne DE, Smartt CT, Ribeiro JM, James AA: The salivary gland-specific apyrase of the mosquito Aedes aegypti is a member of the 5′-nucleotidase family. Proc Natl Acad Sci USA 1995;92:694–698.
  31. Arca B, Lombardo F, de Lara Capurro M, della Torre A, Dimopoulos G, James AA, Coluzzi M: Trapping cDNAs encoding secreted proteins from the salivary glands of the malaria vector Anopheles gambiae. Proc Natl Acad Sci USA 1999;96:1516–1521.
  32. Faudry E, Lozzi SP, Santana JM, D’Souza-Ault M, Kieffer S, Felix CR, Ricart CA, Sousa MV, Vernet T, Teixeira AR: Triatoma infestans apyrases belong to the 5′-nucleotidase family. J Biol Chem 2004;279:19607–19613.
  33. Valenzuela JG, Charlab R, Galperin MY, Ribeiro JM: Purification, cloning, and expression of an apyrase from the bed bug Cimex lectularius. A new type of nucleotide-binding enzyme. J Biol Chem 1998;273:30583–30590.
  34. Valenzuela JG, Belkaid Y, Rowton E, Ribeiro JMC: The salivary apyrase of the blood-sucking sand fly Phlebotomus papatasi belongs to the novel Cimex family of apyrases. J Exp Biol 2001;204:229–237.
  35. Valenzuela JG, Garfield M, Rowton ED, Pham VM: Identification of the most abundant secreted proteins from the salivary glands of the sand fly Lutzomyia longipalpis, vector of Leishmania chagasi. J Exp Biol 200;207:3717–3729.
  36. Champagne DE, Valenzuela JG: Pharmacology of haematophagous arthropod saliva; in Wikel SK (ed): The Immunology of Host-Ectiparasitic Arthropod Relationships. Wallingford, CAB International, 1996.
  37. Francischetti IM, Ribeiro JM, Champagne D, Andersen J: Purification, cloning, expression, and mechanism of action of a novel platelet aggregation inhibitor from the salivary gland of the blood-sucking bug, Rhodnius prolixus. J Biol Chem 2000;275:12639–12650.
  38. Francischetti IM, Andersen JF, Ribeiro JM: Biochemical and functional characterization of recombinant Rhodnius prolixus platelet aggregation inhibitor 1 as a novel lipocalin with high affinity for adenosine diphosphate and other adenine nucleotides. Biochemistry 2002;41:3810–3818.
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    External Resources

  56. Francischetti IM, Valenzuela JG, Pham VM, Garfield MK, Ribeiro JM: Toward a catalog for the transcripts and proteins (sialome) from the salivary gland of the malaria vector Anopheles gambiae. J Exp Biol 2002;205:2429–2451.
  57. Ribeiro JM, Charlab R, Pham VM, Garfield M, Valenzuela JG: An insight into the salivary transcriptome and proteome of the adult female mosquito Culex pipiens quinquefasciatus. Insect Biochem Mol Biol 2004;34:543–563.
  58. Valenzuela JG, Francischetti IM, Pham VM, Garfield MK, Mather TN, Ribeiro JM: Exploring the sialome of the tick Ixodes scapularis. J Exp Biol 2002;205:2843–2864.
  59. Valenzuela JG, Pham VM, Garfield MK, Francischetti IM, Ribeiro JM: Toward a description of the sialome of the adult female mosquito Aedes aegypti. Insect Biochem Mol Biol 2002;32:1101–1122.
  60. Valenzuela JG, Francischetti IM, Pham VM, Garfield MK, Ribeiro JM: Exploring the salivary gland transcriptome and proteome of the Anopheles stephensi mosquito. Insect Biochem Mol Biol 2003;33:717–732.