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Regulator of G-protein signaling protein 18 integrates activating and inhibitory signaling in platelets
Alternative Title
RGS18 is regulated by 14-3-3 binding
Date Issued
2012-04-19
Date Available
2014-09-16T08:38:03Z
Abstract
Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein for the G-α-q and G-α-i subunits of heterotrimeric G-proteins that turns off signaling by G-protein coupled receptors. RGS18 is highly expressed in platelets. In the present study, we show that the 14-3-3γ protein binds to phosphorylated serines 49 and 218 of RGS18. Platelet activation by thrombin, thromboxane A2, or ADP stimulates the association of 14-3-3 and RGS18, probably by increasing the phosphorylation of serine 49. In contrast, treatment of platelets with prostacyclin and nitric oxide, which trigger inhibitory cyclic nucleotide signaling involving cyclic AMP-dependent protein kinase A (PKA) and cyclic GMP-dependent protein kinase I (PKGI), induces the phosphorylation of serine 216 of RGS18 and the detachment of 14-3-3. Serine 216 phosphorylation is able to block 14-3-3 binding to RGS18 even in the presence of thrombin, thromboxane A2, or ADP. 14-3-3-deficient RGS18 is more active compared with 14-3-3-bound RGS18, leading to a more pronounced inhibition of thrombin-induced release of calcium ions from intracellular stores. Therefore, PKA- and PKGI-mediated detachment of 14-3-3 activates RGS18 to block Gq-dependent calcium signaling. These findings indicate cross-talk between platelet activation and inhibition pathways at the level of RGS18 and Gq.
Sponsorship
Science Foundation Ireland
Other Sponsorship
International Society for Advancement of Cytometry (ISAC) Scholar program
Type of Material
Journal Article
Publisher
American Society of Hematology
Journal
Blood
Volume
119
Issue
16
Start Page
3799
End Page
3807
Copyright (Published Version)
2012 American Society of Hematology
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
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