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Reply to “Inhibition of platelet thromboxane receptor function by a thrombin receptor–targeted pepducin”

Nature Medicine volume 9, pages 1447–1448 (2003)Cite this article

Covic et al. reply:

We previously showed that the PAR-4-based pepducin P4pal-10 blocks PAR-4- and PAR-1-dependent signaling and aggregation in human and mouse platelets2. Stampfuss et al. now raise the possibility that P4pal-10 may also inhibit the response of thromboxane receptors8 to low concentrations of a thromboxane receptor agonist. Thromboxane receptors activate G12/13 and Gq signaling pathways in platelets9. Activation of G12/13 causes platelet shape change, and Gq activates phospholipase C-β and intracellular Ca2+ flux. Unlike Stampfuss et al., we have not been able to detect significant inhibition by 3 μM P4pal-10 of U46619-induced shape change or aggregation of gel-filtered human platelets, even at concentrations of U46619 as low as 0.38 μM (unpublished data). We have also measured U46619-dependent activation of Ca2+ flux in washed human platelets prepared by the method of Weber and Schror6. As previously shown, 3 μM P4pal-10 blocks the prolonged Ca2+ response generated by PAR-4 (refs. 2,10). In contrast, we did not detect a significant effect of P4pal-10 on thromboxane receptor–dependent Ca2+ flux induced by 0.1–0.6 μM U46619 (unpublished data). Because we have not observed interference of the PAR-4 pepducin with U46619-induced platelet shape change, aggregation or Ca2+ mobilization, we contend that it is unlikely that this pepducin significantly interferes with thromboxane signaling in platelets.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, 02111, Massachusetts, USA

    Lidija Covic, Suzanne Jacques & Athan Kuliopulos

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  1. Lidija Covic
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  2. Suzanne Jacques
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  3. Athan Kuliopulos
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Tufts-New England Medical Center Hospital has submitted a patent application covering pepducins.

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Covic, L., Jacques, S. & Kuliopulos, A. Reply to “Inhibition of platelet thromboxane receptor function by a thrombin receptor–targeted pepducin”. Nat Med 9, 1447–1448 (2003). https://doi.org/10.1038/nm1203-1447b

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