G-protein Dependent Platelet Signaling - Perspectives for Therapy

Abstract

Platelet activation and aggregation is an integral component of the pathophysiology that leads to thrombotic and ischemic diseases such as cerebral stroke, peripheral vascular disease and myocardial infarction. Anti-platelet agents (such as aspirin, ADP receptor antagonists, and GPIIb/IIIa antagonists), phosphodiesterase inhibitors and anti-coagulants are major part of the current treatment towards treating ischemic diseases. However, their limited efficacy in the setting of arterial thrombosis, unfavorable side effect profile and cost-to-benefit issues substantiate the need for the development of newer and more efficacious antithrombotic drugs. Various platelet agonists like adenosine diphosphate (ADP), thrombin and thromboxane A2 (TXA2) activate platelets by acting via their respective surface receptors, which couple to one or more distinct G-proteins belonging to either the G(i), G(q), G(12/13) or G(s) families. Upon activation, each of these G-proteins trigger a series of intracellular signaling cascades, causing the platelets to undergo shape change, secrete their granular contents, generate positive feedback mediators and form stable platelet aggregates. In addition, various G-protein-mediated signaling cascades act in synergy with one another to amplify the magnitude of the platelet responses. The significance of G-proteins as key mediators of the platelet function and normal hemostasis is further corroborated by extensive gene knockout studies. In this review we will limit our discussion to understanding the role of G-proteins in the process of platelet activation and discuss some of the anti-thrombotic drugs that mediate their beneficial effects by interfering with or preventing the initiation of the G-protein signaling pathway.

Glutathione: new roles in redox signaling for an old antioxidant

“…Moreover, it was reported that supplementing the diet with the antioxidants N -acetylcysteine and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer, by reduction of ROS, DNA damage, and p53 expression (Sayin et al, 2014). On the contrary, the use of small molecules derived from diet that alter the levels of ROS, such as diallyl disulfide, polyphenols, isothiocyanates, and terpenoids has been suggested for the treatment of cancer by promoting ROS generation and GSH depletion in cancer cells (Filomeni et al, 2003; Shankar et al, 2006; Trachootham et al, 2006; Yue et al, 2006; Aquilano et al, 2010). Interestingly, depletion of mitochondrial GSH has also been associated with apoptosis or ATG induced by chemotherapeutic drugs (Samudio et al, 2005; Chen et al, 2011).…”

Determination of the Substrate Specificity of Protein-tyrosine Phosphatase TULA-2 and Identification of Syk as a TULA-2 Substrate

“…First, the protein is phosphorylated on tyrosine in response to GPVI ligation. Second, the phosphorylation event is critical for the physiological function of platelets (25)(26)(27)(28). Third, the protein should contain at least one Tyr(P) site that matches the substrate specificity profile of TULA-2 as revealed by the library screening and kinetic analysis.…”

PI 3-Kinase p110β Regulation of Platelet Integrin αIIbβ3

“…The importance of integrin a IIb b 3 in supporting the hemostatic function of platelets is underscored by the severe bleeding disorder suffered by individuals deficient in this receptor (termed Glanzmann's Thrombasthenia) (Nurden 2005(Nurden , 2006. The conversion of integrin a IIb b 3 to a fully activated state is critically dependent on the generation of one or more soluble agonists at the sites of vascular injury, including adenosine diphosphate (ADP), thromboxane A2 (TXA2), and thrombin (Gachet and Hechler 2005;Hirano 2007;Ruggeri 2002;Shankar et al 2006). Each of these agonists bind to specific G-protein coupled receptors (GPCRs) and stimulate platelet activation through well-defined signaling pathways (Fig.…”