Signaling through Gα 13 Switch Region I Is Essential for Protease-activated Receptor 1-mediated Human Platelet Shape Change, Aggregation, and Secretion *
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 282, Issue: 14, Page: 10210-10222
2007
- 34Citations
- 22Captures
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Metrics Details
- Citations34
- Citation Indexes34
- 34
- CrossRef32
- Captures22
- Readers22
- 22
Article Description
This study investigated the involvement of Gα 13 switch region I (SRI) in protease-activated receptor 1 (PAR1)-mediated platelet function and signaling. To this end, myristoylated peptides representing the Gα 13 SRI (Myr-G 13 SRI pep ) and its random counterpart were evaluated for their effects on PAR1 activation. Initial studies demonstrated that Myr-G 13 SRI pep and Myr-G 13 SRI Random-pep were equally taken up by human platelets and did not interfere with PAR1-ligand interaction. Subsequent experiments revealed that Myr-G 13 SRI pep specifically bound to platelet RhoA guanine nucleotide exchange factor (p115RhoGEF) and blocked PAR1-mediated RhoA activation in platelets and human embryonic kidney cells. These results suggest a direct interaction of Gα 13 SRI with p115RhoGEF and a mechanism for Myr-G 13 SRI pep inhibition of RhoA activation. Platelet function studies demonstrated that Myr-G 13 SRI pep specifically inhibited PAR1-stimulated shape change, aggregation, and secretion in a dose-dependent manner but did not inhibit platelet activation induced by either ADP or A23187. It was also found that Myr-G 13 SRI pep inhibited low dose, but not high dose, thrombin-induced aggregation. Additional experiments showed that PAR1-mediated calcium mobilization was partially blocked by Myr-G 13 SRI pep but not by the Rho kinase inhibitor Y-27632. Finally, Myr-G 13 SRI pep effectively inhibited PAR1-induced stress fiber formation and cell contraction in endothelial cells. Collectively, these results suggest the following: 1) interaction of Gα 13 SRI with p115RhoGEF is required for G 13 -mediated RhoA activation in platelets; 2) signaling through the G 13 pathway is critical for PAR1-mediated human platelet functional changes and low dose thrombin-induced aggregation; and 3) G 13 signaling elicits calcium mobilization in human platelets through a Rho kinase-independent mechanism.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S002192581957692X; http://dx.doi.org/10.1074/jbc.m605678200; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=34249855080&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/17298951; http://www.jbc.org/lookup/doi/10.1074/jbc.M605678200; https://syndication.highwire.org/content/doi/10.1074/jbc.M605678200; https://linkinghub.elsevier.com/retrieve/pii/S002192581957692X; https://dx.doi.org/10.1074/jbc.m605678200
American Society for Biochemistry & Molecular Biology (ASBMB)
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