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Calcium Mobilization in Human Platelets is Differentially Modulated by PAR‐1 and PAR‐4 through Gi/o and PI3K
Author(s) -
Voss Bryan Martin,
Hamm Heidi E
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a118-a
Subject(s) - heterotrimeric g protein , platelet , protease activated receptor , platelet activation , microbiology and biotechnology , thrombin , receptor , integrin , chemistry , thrombin receptor , platelet membrane glycoprotein , pi3k/akt/mtor pathway , g protein coupled receptor , glycoprotein ib , signal transduction , g protein , biology , biochemistry , immunology
Protease activated receptors (PARs) on the platelet surface play an essential role in mediating hemostasis. Human platelets express PAR‐1 and PAR‐4, and these receptor subtypes are activated by thrombin. Knockout mice for the various G‐alpha subunits of the heterotrimeric G‐protein family have provided good tools for the study of PAR‐4 signaling in platelets. However, differences in G‐protein coupling between human and mouse PAR‐4 could exist, and mouse platelets do not express PAR‐1. Therefore, determining which G‐alpha subunits PAR‐1 and PAR‐4 activate in human platelets is paramount in understanding the physiological effects of thrombin and its inhibitors. Both receptors have been shown to couple to Gq and G12/13 pathways. However, neither receptor has been shown to have a Gi/o signaling component. The main objective of our research was to determine the role of Gi/o in human platelet PAR‐mediated calcium mobilization and integrin activation. We have found that PAR‐1, but not PAR‐4, directly couples to Gi/o family members to activate PI3K in human platelets using flow cytometry. We have also shown that this PI3K potentiates intraplatelet calcium mobilization in a conditional manner using Fura‐2 loaded platelets, and also causes integrin glycoprotein IIbIIIa activation using flow cytometry. PAR‐4 seems to lack this Gi/o pathway, and we are currently developing a cell permeable peptide based strategy to explore this possibility. Demonstration of a Gi/o signaling component downstream of PAR‐1 in human platelets is a novel finding with potential therapeutic implications. This work was supported by the Training Grant in the Pharmacological Sciences (Vanderbilt‐NIH).