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Coordinate activation of human platelet protease-activated receptor-1 and -4 in response to subnanomolar alpha-thrombin.
J Biol Chem. 2008 Oct 03; 283(40):26886-93.JB

Abstract

We previously demonstrated that human platelets activated with SFLLRN release PAR-1 activation peptide, PAR-1-(1-41), even in the presence of hirudin. This observation suggests that during their activation, platelets generate a protease that activates PAR-1. In this study, PAR-1 and -4 activation peptides were detected 10 s after <or=1.0 nm alpha-thrombin, 10 microm SFLLRN, or 100 microm AYPGKF were added to platelets. When SFLLRN or AYGPKF were added to platelets, generation of PAR-1 and -4 activation peptides was complete at 10 s. Generation of both PAR-1 and -4 activation peptides in response to 1 nm alpha-thrombin was significantly inhibited by affinity-purified anti-PAR-1-(35-62) IgY, anti-PAR-4-(34-54) IgY, and by the specific PAR-1 antagonist BMS 200261, but not by the PAR-4 antagonist YD3. Effective inhibition of platelet aggregation in response to 1.0 nm alpha-thrombin occurred only in the presence of both anti-PAR span antibodies. We conclude that platelet activation initiated with <or=1.0 nm alpha-thrombin proceeds via simultaneous PAR-1 and -4 activation. Inhibiting the activation of either PAR inhibits activation of the other. Both PAR-1 and -4 activation must be inhibited to prevent platelet activation subsequent to thrombin binding to platelets. The more efficient generation of PAR activation peptides by platelets activated with SFLLRN or AYGPKF, compared with alpha-thrombin, indicates that a platelet-derived serine protease that is inactivated by soybean trypsin inhibitor propagates PAR-1 and -4 activation.

Authors+Show Affiliations

Canadian Blood Services, Hamilton, Ontario, Canada. ofosuf@mcmaster.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18682394

Citation

Ofosu, Frederick A., et al. "Coordinate Activation of Human Platelet Protease-activated Receptor-1 and -4 in Response to Subnanomolar Alpha-thrombin." The Journal of Biological Chemistry, vol. 283, no. 40, 2008, pp. 26886-93.
Ofosu FA, Dewar L, Craven SJ, et al. Coordinate activation of human platelet protease-activated receptor-1 and -4 in response to subnanomolar alpha-thrombin. J Biol Chem. 2008;283(40):26886-93.
Ofosu, F. A., Dewar, L., Craven, S. J., Song, Y., Cedrone, A., Freedman, J., & Fenton, J. W. (2008). Coordinate activation of human platelet protease-activated receptor-1 and -4 in response to subnanomolar alpha-thrombin. The Journal of Biological Chemistry, 283(40), 26886-93. https://doi.org/10.1074/jbc.M802237200
Ofosu FA, et al. Coordinate Activation of Human Platelet Protease-activated Receptor-1 and -4 in Response to Subnanomolar Alpha-thrombin. J Biol Chem. 2008 Oct 3;283(40):26886-93. PubMed PMID: 18682394.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coordinate activation of human platelet protease-activated receptor-1 and -4 in response to subnanomolar alpha-thrombin. AU - Ofosu,Frederick A, AU - Dewar,Lori, AU - Craven,Sharon J, AU - Song,Yingqi, AU - Cedrone,Aisha, AU - Freedman,John, AU - Fenton,John W,2nd Y1 - 2008/08/05/ PY - 2008/8/7/pubmed PY - 2008/11/5/medline PY - 2008/8/7/entrez SP - 26886 EP - 93 JF - The Journal of biological chemistry JO - J Biol Chem VL - 283 IS - 40 N2 - We previously demonstrated that human platelets activated with SFLLRN release PAR-1 activation peptide, PAR-1-(1-41), even in the presence of hirudin. This observation suggests that during their activation, platelets generate a protease that activates PAR-1. In this study, PAR-1 and -4 activation peptides were detected 10 s after <or=1.0 nm alpha-thrombin, 10 microm SFLLRN, or 100 microm AYPGKF were added to platelets. When SFLLRN or AYGPKF were added to platelets, generation of PAR-1 and -4 activation peptides was complete at 10 s. Generation of both PAR-1 and -4 activation peptides in response to 1 nm alpha-thrombin was significantly inhibited by affinity-purified anti-PAR-1-(35-62) IgY, anti-PAR-4-(34-54) IgY, and by the specific PAR-1 antagonist BMS 200261, but not by the PAR-4 antagonist YD3. Effective inhibition of platelet aggregation in response to 1.0 nm alpha-thrombin occurred only in the presence of both anti-PAR span antibodies. We conclude that platelet activation initiated with <or=1.0 nm alpha-thrombin proceeds via simultaneous PAR-1 and -4 activation. Inhibiting the activation of either PAR inhibits activation of the other. Both PAR-1 and -4 activation must be inhibited to prevent platelet activation subsequent to thrombin binding to platelets. The more efficient generation of PAR activation peptides by platelets activated with SFLLRN or AYGPKF, compared with alpha-thrombin, indicates that a platelet-derived serine protease that is inactivated by soybean trypsin inhibitor propagates PAR-1 and -4 activation. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18682394/Coordinate_activation_of_human_platelet_protease_activated_receptor_1_and__4_in_response_to_subnanomolar_alpha_thrombin_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&amp;pmid=18682394 DB - PRIME DP - Unbound Medicine ER -