P2X1-mediated ERK2 Activation Amplifies the Collagen-induced Platelet Secretion by Enhancing Myosin Light Chain Kinase Activation

Tóth-Zsámboki, Emese; Oury, Cécile; Cornelissen, Heidi; Vos, Rita De; Vermylen, Jos; Hoylaerts, Marc

doi:10.1074/jbc.m308452200

Cited by 76 publications

(86 citation statements)

References 32 publications

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“…Noteworthily, in platelets, P2X 1 -triggered Ca 2ϩ influx causes CaM-and MLC kinase-dependent increase of MLC phosphorylation, leading to cell shape change (26). Although we cannot rule out the possibility that P2X 1 could also signal through Ca 2ϩ -dependent pathways independently of RhoA, it would be interesting to determine whether Ca 2ϩ -and CaM-dependent protein kinase-dependent mechanisms of RhoA activation exist in neutrophils.…”

Section: Discussionmentioning

confidence: 95%

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

Lecut

Frederix

Johnson

et al. 2009

The Journal of Immunology

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ATP, released at the leading edge of migrating neutrophils, amplifies chemotactic signals. The aim of our study was to investigate whether neutrophils express ATP-gated P2X1 ion channels and whether these channels could play a role in chemotaxis. Whole-cell patch clamp experiments showed rapidly desensitizing currents in both human and mouse neutrophils stimulated with P2X1 agonists, αβ-methylene ATP (αβMeATP) and βγMeATP. These currents were strongly impaired or absent in neutrophils from P2X1−/− mice. In Boyden chamber assays, αβMeATP provoked chemokinesis and enhanced formylated peptide- and IL-8-induced chemotaxis of human neutrophils. This agonist similarly increased W-peptide-induced chemotaxis of wild-type mouse neutrophils, whereas it had no effect on P2X1−/− neutrophils. In human as in mouse neutrophils, αβMeATP selectively activated the small RhoGTPase RhoA that caused reversible myosin L chain phosphorylation. Moreover, the αβMeATP-elicited neutrophil movements were prevented by the two Rho kinase inhibitors, Y27632 and H1152. In a gradient of W-peptide, P2X1−/− neutrophils migrated with reduced speed and displayed impaired trailing edge retraction. Finally, neutrophil recruitment in mouse peritoneum upon Escherichia coli injection was enhanced in wild-type mice treated with αβMeATP, whereas it was significantly impaired in the P2X1−/− mice. Thus, activation of P2X1 ion channels by ATP promotes neutrophil chemotaxis, a process involving Rho kinase-dependent actomyosin-mediated contraction at the cell rear. These ion channels may therefore play a significant role in host defense and inflammation.

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Section: Discussionmentioning

confidence: 95%

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

Lecut

Frederix

Johnson

et al. 2009

The Journal of Immunology

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“…With other agonists, such as low doses of collagen (20) or thrombin (21), ERK2 is involved in platelet aggregation. In these conditions, ERK2 acts on platelet secretion and activation of myosin light chain kinase (20,22).…”

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confidence: 99%

Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

Kauskot

Adam

Mazharian

et al. 2007

Journal of Biological Chemistry

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The involvement of the mitogen-activated protein kinase c-Jun NH 2 -terminal kinase-1 (JNK1) has never been investigated in hemostasis and thrombosis. Using two JNK inhibitors (SP600125 and 6o), we have demonstrated that JNK1 is involved in collagen-induced platelet aggregation dependent on ADP. In these conditions, JNK1 activation requires the coordinated signaling pathways of collagen receptors (␣2␤1 and glycoprotein (GP)VI) and ADP. In contrast, JNK1 is not required for platelet adhesion on a collagen matrix in static or blood flow conditions (300 -1500 s ؊1 ) involving collagen receptors (␣2␤1 and GPVI). Importantly, at 1500 s ؊1 , JNK1 acts on thrombus formation on a collagen matrix dependent on GPIb-von Willebrand factor (vWF) interaction but not ADP receptor activation. This is confirmed by the involvement of JNK1 in shear-induced platelet aggregation at 4000 s ؊1 . We also provide evidence during rolling and adhesion of platelets to vWF that platelet GPIb-vWF interaction triggers ␣IIb␤3 activation in a JNK1-dependent manner. This was confirmed with a Glanzmann thrombastenic patient lacking ␣IIb␤3. Finally, in vivo, JNK1 is involved in arterial but not in venular thrombosis in mice. Overall, our in vitro studies define a new role of JNK1 in thrombus formation in flowing blood that is relevant to thrombus development in vivo.

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“…The P2X 1 -PKC-ERK2 pathway plays a role in amplifying dense granule release, an event needed for completion of platelet aggregation upon mild stimulation with collagen. Furthermore, we found that α,β-meATP causes rapid, transient (2-5 s), and dosedependent myosin light chain (MLC) phosphorylation [149]. Phosphorylation was inhibited by the calmodulin (CaM) inhibitor W-7, but not by the Rho kinase inhibitor HA-1077, i.e.…”

Section: The Platelet P2x 1 Receptor For Atpmentioning

confidence: 84%

The Platelet ATP and ADP Receptors

Oury

Tóth-Zsámboki

Vermylen

et al. 2006

CPD

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Adenine nucleotides, ADP and ATP, are coreleased from dense granules during platelet activation, as well as from endothelial cells and damaged red blood cells following vascular injury. Through autocrine and paracrine mechanisms, these extracellular signaling molecules interact with the platelet P2 receptors to amplify ongoing platelet activation. Two receptors for ADP, the G q -protein-coupled P2Y 1 and G i -protein-coupled P2Y 12 and one receptor for ATP, the P2X 1 ion channel, have been identified on platelets. Due to distinct pharmacological properties and differential regulation, the P2Y and P2X receptors essentially operate on different scales of time and distance and trigger selective intracellular signaling cascades. Recent advances in the understanding of the P2Y receptor physiology have reinforced the concept of these receptors as useful targets for antithrombotic therapy. The function of P2X 1 in platelet activation only recently started to be unraveled. This review focuses on recent findings on the physiology of these platelet ADP and ATP receptors, their distinct downstream intracellular signaling pathways as well as on the available agonists, antagonists and inhibitors that allow their pharmacological discrimination.Key Words: Hemostasis, thrombosis, adenine nucleotides, P2Y 1 , P2Y 12 , P2X 1 , antithrombotic therapy. HISTORY AND CLASSIFICATION OF PURINERGIC RECEPTORSThe first report about the potent actions of an adenine compound, AMP, extracted from heart muscle, was published by Drury and Szent-Györgyi in 1929. Initial investigations focused on effects of adenosine and ATP on the heart and vasculature, or concerned the effects of purines on platelets [1] and on mast cells. Further insights into the physiological role of extracellular purines and pyrimidines were provided via the study of their biological sources [2]. In this respect, the detection of nucleotide release from the heart during hypoxia [3] or from skeletal muscle during contraction indicated that secretion of purine compounds might be coupled to metabolic demand to regulate local blood flow. ATP release from sensory nerves suggested that adenine nucleotides play a role as neurotransmitter or neuromodulator in the central and peripheral nervous system [4].These early publications established that purinergic nucleotides act as extracellular signaling molecules [5]. Nucleotides are now documented to contribute to a diverse range of physiological responses such as smooth muscle contraction, neurotransmission, exocrine and endocrine secretion, immune response, inflammation, platelet aggregation, male reproduction, nociception and modulation of cardiac function [6].Purines and pyrimidines mediate their effects by interacting with distinct cell-surface receptors. Purinergic receptors were first formally recognized by Burnstock in 1978 [7]. They were divided into two classes: at P1-purinoceptors adenosine is the principal natural ligand, while P2-purinoceptors recognize both purine and pyrimidine nucleotides Based on an increasin...

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P2X1-mediated ERK2 Activation Amplifies the Collagen-induced Platelet Secretion by Enhancing Myosin Light Chain Kinase Activation

Cited by 76 publications

References 32 publications

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

The Platelet ATP and ADP Receptors

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