Prostacyclin and Sodium Nitroprusside Inhibit the Activity of the Platelet Inositol 1,4,5-Trisphosphate Receptor and Promote Its Phosphorylation

Cavallini, Lucia; Coassin, Mariagrazia; Borean, Alessio; Alexandre, Adolfo

doi:10.1074/jbc.271.10.5545

Cited by 131 publications

(91 citation statements)

References 61 publications

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“…On one hand, PKA enhances the effects of InsP 3 on purified reconstituted cerebellar type I receptors (40) and appears to enhance InsP 3 action in intact hepatocytes (41). On the other hand, PKA inhibits the effects of InsP 3 on cerebellar microsomes (42) and appears to decrease sensitivity to InsP 3 in platelets (43) and trachea (44). Our studies indicate that PKA causes a modest (ϳ20%) enhancement of InsP 3 potency in SH-SY5Y, AR4 -2J, and RINm5F cells and also enhances by ϳ10% the maximal effect of InsP 3 in SH-SY5Y cells.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Inositol 1,4,5-Trisphosphate Receptors by cAMP-dependent Protein Kinase

Wojcikiewicz

Luo

1998

Journal of Biological Chemistry

147

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The ability of cAMP-dependent protein kinase (PKA) to phosphorylate type I, II, and III inositol 1,4,5-trisphosphate (InsP 3 ) receptors was examined. The receptors either were immunopurified from cell lines and then phosphorylated with purified PKA or were phosphorylated in intact cells after activating intracellular cAMP formation. The former studies showed that the type I receptor was a good substrate for PKA (0.65 mol P i incorporated/mol receptor), whereas type II and III receptors were phosphorylated relatively weakly. The latter studies showed that despite these differences, each of the receptors was phosphorylated in intact cells in response to forskolin or activation of neurohormone receptors. Detailed examination of SH-SY5Y neuroblastoma cells, which express >99% type I receptor, revealed that minor increases in cAMP concentration were sufficient to cause maximal phosphorylation. Thus, VIP and pituitary adenylyl cyclase activating peptide (acting through G s -coupled pituitary adenylyl cyclase activating peptide-I receptors) were potent stimuli of type I receptor phosphorylation, and remarkably, even slight increases in cAMP concentration induced by carbachol (acting through G q -coupled muscarinic receptors) or other Ca 2؉ mobilizing agents were sufficient to cause phosphorylation. Finally, PKA enhanced InsP 3 -induced Ca 2؉ mobilization in a range of permeabilized cell types, irrespective of whether the type I, II, or III receptor was predominant. In summary, these data show that all InsP 3 receptors are phosphorylated by PKA, albeit with marked differences in stoichiometry. The ability of both G s -and G q -coupled cell surface receptors to effect InsP 3 receptor phosphorylation by PKA suggests that this process is widespread in mammalian cells and provides multiple routes by which the cAMP signaling pathway can influence Ca 2؉ mobilization.Inositol 1,4,5-trisphosphate (InsP 3 ) 1 receptors form tetrameric channels in endoplasmic reticulum membranes that conduct Ca 2ϩ in an InsP 3 -sensitive manner (1-3). Thus, they link cell surface receptor-mediated increases in InsP 3 formation to increases in cytoplasmic free Ca 2ϩ concentration ([Ca 2ϩ ] i ). To date, the coding regions of three mammalian InsP 3 receptor genes have been sequenced (4 -11). Their products, termed type I, II, and III receptors, are ϳ2700 amino acids in length and are 60 -70% identical at the amino acid level (2-11). Each receptor is thought to have the same overall structure, being divided into three domains: an N-terminal ligand binding domain, a C-terminal channel forming domain, and an intervening sequence, termed the coupling domain, that contains sites either known or hypothesized to be involved in receptor regulation (2-4, 6, 12). Type I, II, and III receptors are expressed in different amounts in different cell types, and some cells co-express all three receptors (13,14). InsP 3 receptors form heterotetramers in intact cells, and such associations persist after receptor solubilization (14 -17).Characterization of diffe...

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Inositol 1,4,5-Trisphosphate Receptors by cAMP-dependent Protein Kinase

Wojcikiewicz

Luo

1998

Journal of Biological Chemistry

147

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“…On the other hand, in a series of nonendothelial cell types, NO has been reported to modify almost all Ca 2ϩ i -elevating and Ca 2ϩ i -sequestrating components (19,20). NO attenuates IICR at several steps, by inhibiting G-protein in VSMCs (21) and platelets (22), by inhibiting phospholipase ␤ in PC12 cells (23), and by inhibiting IP 3 receptors in VSMCs (24). The effects of NO on CCE vary among cell types (19,20,(25)(26)(27)(28)(29)(30); NO potentiates CCE in pancreatic acinar cells (25)(26)(27) and colonic epithelial cells (28), does not affect CCE in Jurkat T-lymphocytes (29) and embryonic kidney cells (30), and inhibits CCE in platelets (31) and VSMCs (32).…”

Section: Elevation No Also Potentiated Camentioning

confidence: 99%

Autocrine Action and Its Underlying Mechanism of Nitric Oxide on Intracellular Ca2+ Homeostasis in Vascular Endothelial Cells

Chen¹,

Wang²,

Wang³

et al. 2000

Journal of Biological Chemistry

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“…6 The cGMP-dependent protein kinase type I (cGKI) is strictly required for inhibition of platelet activation by NO/cGMP. 2,7 Although cGKI has been reported to inhibit intracellular Ca 2ϩ release in platelets, [8][9][10] the exact molecular targets downstream of cGKI involved in NO/cGMP-dependent inhibition of platelet activation have not been defined.In smooth muscle cells, we have identified the cGKI substrate IRAG 4, ] receptorassociated cGKI substrate protein), a 125-kDa protein which copurifies in a macrocomplex together with cGKI and the InsP 3 receptor type I (InsP 3 RI). 11 IRAG is essential for NO/cGMPdependent smooth muscle cell relaxation, because it negatively regulates InsP 3 -induced calcium release.…”

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confidence: 99%

IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation

Antl¹,

Brühl

Eiglsperger³

et al. 2006

Blood

135

148

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Defective regulation of platelet activation/ aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke. A central regulatory pathway conveying inhibition of platelet activation/aggregation is nitric oxide (NO)/cyclic GMP (cGMP) signaling by cGMP-dependent protein kinase I (cGKI). However, the regulatory cascade downstream of cGKI mediating platelet inhibition is still unclear. Here, we show that the inositol-1,4,5-trisphosphate receptor- IntroductionPlatelet activation and aggregation at foci of vascular injury is essential for primary hemostasis, but it also initiates arterial thrombosis, the leading cause of myocardial infarction and stroke. 1 The gaseous molecule nitric oxide (NO) is an endogenous platelet antagonist and inhibits platelet activation and aggregate formation both in vitro and in vivo. [2][3][4] NO activates soluble guanylyl cyclases that initiate a subsequent rise in platelet cyclic GMP (cGMP). 2,3 Several mechanisms have been proposed by which NO/cGMP signaling abolishes platelet activation and aggregation, including inhibition of G-proteincoupled receptors and rearrangement of the cytoskeleton. 3,5 In addition, NO/cGMP prevents inositol-1,4,5-trisphosphate (InsP 3 )-mediated intracellular calcium release, 3,5 the critical step in the signal transduction pathway that leads to full platelet activation. 6 The cGMP-dependent protein kinase type I (cGKI) is strictly required for inhibition of platelet activation by NO/cGMP. 2,7 Although cGKI has been reported to inhibit intracellular Ca 2ϩ release in platelets, [8][9][10] the exact molecular targets downstream of cGKI involved in NO/cGMP-dependent inhibition of platelet activation have not been defined.In smooth muscle cells, we have identified the cGKI substrate IRAG 4, ] receptorassociated cGKI substrate protein), a 125-kDa protein which copurifies in a macrocomplex together with cGKI and the InsP 3 receptor type I (InsP 3 RI). 11 IRAG is essential for NO/cGMPdependent smooth muscle cell relaxation, because it negatively regulates InsP 3 -induced calcium release. 11,12 Because of the importance of cGKI signaling in platelets, we studied here the expression and cGKI-dependent phosphorylation of IRAG in platelets and the physiologic relevance of the IRAG-InsP 3 RI interaction for the regulation of platelet function. We provide first evidence that the IRAG-InsP 3 RI interaction mediates NO/cGMP-dependent inhibition of thrombin-induced increases in [Ca 2ϩ ] i in platelets and is the major determinant of NO/cGMPdependent prevention of platelet aggregation in vitro and arterial thrombosis in vivo. Materials and methods MaterialsWe used 8-pCPT-cGMP, Rp-8-Br-PET-cGMPS, Sp-5,6-DCl-cBIMPS (cBIMPS), 8-AET-cGMP-agarose, ethanolamine-agarose (Biolog, Bremen, Germany), forskolin (Calbiochem, Darmstadt, Germany), prostacyclin (Sigma, Deisenhofen, Germany), iloprost (Axxora, San Diego, CA), DEA/NO (Axxora), NO-spermine (Axxora), GEA-NO 3162 (Axxora), sodium nitroprusside (...

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Prostacyclin and Sodium Nitroprusside Inhibit the Activity of the Platelet Inositol 1,4,5-Trisphosphate Receptor and Promote Its Phosphorylation

Cited by 131 publications

References 61 publications

Phosphorylation of Inositol 1,4,5-Trisphosphate Receptors by cAMP-dependent Protein Kinase

Phosphorylation of Inositol 1,4,5-Trisphosphate Receptors by cAMP-dependent Protein Kinase

Autocrine Action and Its Underlying Mechanism of Nitric Oxide on Intracellular Ca2+ Homeostasis in Vascular Endothelial Cells

IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation

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