Signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation

Schinner, Elisabeth; Salb, Katharina; Schlossmann, Jens

doi:10.3109/09537104.2010.544151

Cited by 28 publications

(41 citation statements)

References 38 publications

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“…IRAG exists in a complex with cGK-I and the type 1 InsP 3 receptor in the membrane of the dense tubular system and regulates InsP 3 -mediated calcium release, a major component of aggregation and secretion responses to many agonists, including thrombin. IRAG deletion (14), or mutation to prevent its association with the InsP 3 receptor, strongly blunts the inhibitory effects of NO donors on platelets (12). In comparison, deletion of other putative targets of platelet cGMP, such as VASP, causes more modest reductions in sensitivity to NO and cGMP (30).…”

Section: P2y 12 Receptor Blockade Greatly Increases the Inhibition Ofmentioning

confidence: 99%

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Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide

Kirkby

Lundberg

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Circulating platelets are constantly exposed to nitric oxide (NO) released from the vascular endothelium. This NO acts to reduce platelet reactivity, and in so doing blunts platelet aggregation and thrombus formation. For successful hemostasis, platelet activation and aggregation must occur at sites of vascular injury despite the constant presence of NO. As platelets aggregate, they release secondary mediators that drive further aggregation. Particularly significant among these secondary mediators is ADP, which, acting through platelet P2Y 12 receptors, strongly amplifies aggregation. Platelet P2Y 12 receptors are the targets of very widely used antithrombotic drugs such as clopidogrel, prasugrel, and ticagrelor. Here we show that blockade of platelet P2Y 12 receptors dramatically enhances the antiplatelet potency of NO, causing a 1,000-to 100,000-fold increase in inhibitory activity against platelet aggregation and release reactions in response to activation of receptors for either thrombin or collagen. This powerful synergism is explained by blockade of a P2Y 12 receptor-dependent, NO/cGMPinsensitive phosphatidylinositol 3-kinase pathway of platelet activation. These studies demonstrate that activation of the platelet ADP receptor, P2Y 12 , severely blunts the inhibitory effects of NO. The powerful antithrombotic effects of P2Y 12 receptor blockers may, in part, be mediated by profound potentiation of the effects of endogenous NO.anti-platelet therapy | atherothrombosis | prostacyclin A ctivation of platelets in a damaged blood vessel leads to a well-characterized sequence of events, including the important release of secondary mediators of aggregation, notably ADP and thromboxane A 2 (1-3). These mediators are the targets of antithrombotic drugs taken by many millions of patients as prophylactic protection against heart attacks and strokes. In particular, inhibition of thromboxane A 2 production by aspirin explains the antithrombotic utility of this drug, whereas blockade of the ADP receptor, P2Y 12 , by drugs such as clopidogrel, prasugrel, and ticagrelor provides a second, and possibly even stronger, antithrombotic protection (4). Within the circulation, platelets are constantly exposed to antithrombotic mediators, notably prostaglandin I 2 (PGI 2 ), which is derived from the vascular endothelium, and nitric oxide (NO), which can be produced by the vascular endothelium (5) and platelets themselves (6, 7). This leads to the understanding that there is an important interplay between endothelial-derived antiaggregatory mediators and platelet-derived proaggregatory mediators. For example, it has been demonstrated that activation of platelet P2Y 12 receptors by ADP causes inhibition of platelet adenylyl cyclase, which reduces the ability of PGI 2 acting through prostaglandin IP receptors to elevate cAMP, and thus reduces platelet aggregation. Hence, blockade of platelet P2Y 12 receptors increases the sensitivity of platelets to the antiaggregatory and antisecretory effects of PGI 2 (8, 9). This interaction is re...

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Section: P2y 12 Receptor Blockade Greatly Increases the Inhibition Ofmentioning

confidence: 99%

“…Compared with PGI 2 , NO is less potent as an inhibitor of platelet activation (10)(11)(12)(13)(14)(15)(16)(17). NO acts by directly activating platelet guanylyl cyclase, causing an increase in intraplatelet cGMP (13).…”

mentioning

confidence: 99%

Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide

Kirkby

Lundberg

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…A functional difference of these splice variants was not revealed so far. IRAG targets PKG1␤ to the ER and additionally binds with its coiled-coil domain to the ino- (2,20,28,73). IRAG function.…”

Section: Irag As Pkg Target: Signaling and Functionmentioning

confidence: 99%

IRAG and novel PKG targeting in the cardiovascular system

Schlossmann

Desch

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Schlossmann J, Desch M. IRAG and novel PKG targeting in the cardiovascular system. Am J Physiol Heart Circ Physiol 301: H672-H682, 2011. First published June 10, 2011; doi:10.1152/ajpheart.00198.2011.-Signaling by nitric oxide (NO) determines several cardiovascular functions including blood pressure regulation, cardiac and smooth muscle hypertrophy, and platelet function. NO stimulates the synthesis of cGMP by soluble guanylyl cyclases and thereby activates cGMP-dependent protein kinases (PKGs), mediating most of the cGMP functions. Hence, an elucidation of the PKG signaling cascade is essential for the understanding of the (patho)physiological aspects of NO. Several PKG signaling pathways were identified, meanwhile regulating the intracellular calcium concentration, mediating calcium desensitization or cytoskeletal rearrangement. During the last decade it emerged that the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG), an endoplasmic reticulum-anchored 125-kDa membrane protein, is a main signal transducer of PKG activity in the cardiovascular system. IRAG interacts specifically in a trimeric complex with the PKG1␤ isoform and the inositol 1,4,5-trisphosphate receptor I and, upon phosphorylation, reduces the intracellular calcium release from the intracellular stores. IRAG motifs for phosphorylation and for targeting to PKG1␤ and 1,4,5-trisphosphate receptor I were identified by several approaches. The (patho)physiological functions for the regulation of smooth muscle contractility and the inhibition of platelet activation were perceived. In this review, the IRAG recognition, targeting, and function are summarized compared with PKG and several PKG substrates in the cardiovascular system. inositol trisphosphate receptor-associated guanosine 3=,5=-cyclic monophosphatekinase substrate; nitric oxide; guanosine 3=,5=-cyclic monophosphate-dependent protein kinase THIS ARTICLE is part of a collection on Hypertension and Novel Modulators of Vascular Tone. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.Nitric oxide (NO) leads to cGMP synthesis and thereby activates cGMP-dependent protein kinase (PKG), mediating various cardiovascular functions. The identification of PKG substrates including the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG) has lead to a new view of PKG1 isozyme PKG1␤ and PKG1␣ function. Intracellular targeting and function of these isozymes are modulated by different substrates. The recognition of these substrates is mediated by the NH 2 -terminal leucine/isoleucine zipper (LZ) domains of PKG1. In this review the current view of the molecular interaction and function of IRAG compared with other substrates regulated by PKG are described, mainly focusing on the cardiovascular system. Furthermore, the subtle pathways for cGMP/PKG signaling are discussed. Function of NO/cGMP/PKG Signaling CascadeNO/cGMP signaling regulates several tasks in the cardiovascular sy...

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“…The concentration of PKG I in human platelets is 3.65μM, which is higher than that of any other cell type examined (Antl et al, 2007;Eigenthaler et al, 1992). In PKG-deficient murine platelets the inhibition of the cGMP analog on granule secretion, aggregation and adhesion is severely affected (Massberg et al 1999;Schinner et al, 2011). The effect of PKG may be in part mediated by IRAG.…”

Section: Anti-platelet Aggregation Actionmentioning

confidence: 92%

cGMP-Dependent Protein Kinase in the Regulation of Cardiovascular Functions

Gao¹,

Dou²,

Xue³

et al. 2012

Protein Kinases

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Signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation

Cited by 28 publications

References 38 publications

Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide

Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide

IRAG and novel PKG targeting in the cardiovascular system

cGMP-Dependent Protein Kinase in the Regulation of Cardiovascular Functions

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Signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation

Cited by 28 publications

References 38 publications

Blockade of the purinergic P2Y 12 receptor greatly increases the platelet inhibitory actions of nitric oxide

Blockade of the purinergic P2Y 12 receptor greatly increases the platelet inhibitory actions of nitric oxide

IRAG and novel PKG targeting in the cardiovascular system

cGMP-Dependent Protein Kinase in the Regulation of Cardiovascular Functions

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Product

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Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide

Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide