Regulator of G-protein signaling protein 18 integrates activating and inhibitory signaling in platelets

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Title: Regulator of G-protein signaling protein 18 integrates activating and inhibitory signaling in platelets
Authors: Gegenbauer, Kristina
Elia, Giuliano
Blanco-Fernandez, Alfonso
Smolenski, Albert P.
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Date: 19-Apr-2012
Online since: 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.
Funding Details: Science Foundation Ireland
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
Keywords: RGS18Phosphorylated serinesPlatelet aggregationThrombopoiesis
DOI: 10.1182/blood-2011-11-390369
Language: en
Status of Item: Peer reviewed
Appears in Collections:Medicine Research Collection

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