P2Y1, P2Y2, P2Y4, and P2Y6receptors are coupled to Rho and Rho kinase activation in vascular myocytes

Sauzeau, Vincent; Jeune, Hélène Le; Cario‐Toumaniantz, Chrystelle; Vaillant, Nathalie; Gadeau, Alain‐Pierre; Des̀granges, Claude; Scalbert, Elizabeth; Chardin, Pierre Teilhard de; Pacaud, Pierre; Loirand, Gervaise

doi:10.1152/ajpheart.2000.278.6.h1751

Cited by 102 publications

(91 citation statements)

References 31 publications

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“…In keeping with these data, P2Y 2 has previously been shown to be coupled to Rho kinase activation in vascular myocytes and 1321N1 astrocy-toma cells (Sauzeau et al, 2000;Liao et al, 2007). The involvement of the endothelial Rho kinase in LPS-induced neutrophil migration in our model was confirmed with Y27632, a selective inhibitor of this enzyme.…”

Section: Discussionsupporting

confidence: 87%

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Kukulski

Yebdri

Bahrami

et al. 2010

Molecular Immunology

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Previous studies showed that P2 receptors are involved in neutrophil migration via stimulation of chemokine release and by facilitating chemoattractant gradient sensing. Here, we have investigated whether these receptors are involved in LPS-induced neutrophil transendothelial migration (TEM) using a Boyden chamber where neutrophils migrated through a layer of lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs). In line with a role of P2 receptors, neutrophil TEM was inhibited by the P2 receptor antagonists suramin and reactive blue 2 (RB-2) acting on the basolateral, but not luminal, HUVECs' P2 receptors. HUVECs express P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 and P2Y 11 . The involvement of P2Y 4 was unlikely as this receptor is insensitive to suramin while P2Y 1 , P2Y 6 and P2Y 11 were excluded with available selective antagonists, leaving P2Y 2 as the only candidate. Indeed, the P2Y 2 knockdown in HUVECs inhibited neutrophil TEM compared to control HUVECs transfected with scrambled siRNA. Moreover, UTP, a P2Y 2 ligand, markedly potentiated LPS-induced TEM. Interestingly, IL-8 and ICAM-1 had a modest effect on neutrophil TEM in this 3 h assay which was significantly diminished by the inhibition of Rho kinase in HUVECs with Y27632. In summary, endothelial P2Y 2 receptors control the early LPSinduced neutrophil TEM in vitro via Rho kinase activation.

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Section: Discussionsupporting

confidence: 87%

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Kukulski

Yebdri

Bahrami

et al. 2010

Molecular Immunology

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“…5A, lower panel). The time-course of P2Y 1 -induced RhoA activation shared a close similarity to that of activation in vascular myocytes (28). The RhoA activation, however, was more robust when it was activated by ATP rather than by 2-MeSADP.…”

Section: Resultssupporting

confidence: 52%

“…23), which is in line with the activity-dependence of the reshaping of synaptic architecture at the nmjs (4). On the other hand, the application of P2Y 1 receptor agonists activated the membrane-bound RhoA and stimulated the actin cytoskeleton organization in cultured vascular myocytes (28). In the present study, we provide evidence that the activation of P2Y 1 receptors induced the formation of membrane-bound RhoA, which subsequently potentiated the agrin-induced AChR aggregation on post-synaptic muscle fibers.…”

supporting

confidence: 74%

“…Here, we demonstrate further the potentiation role of P2Y 1 receptor in agrininduced AChR aggregation could also involve the small GTPases. In cultured vascular myocytes, the activation of P2Y receptors including P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 are known to induce RhoA and RhoA kinase activation, formation of actin stress fiber and an increase in F-to G-actin ratio (28). Similar to the action of agrin, P2Y 1 receptor is also involved in the transient activation of RhoA and Rac in cultured myotubes.…”

Section: Discussionmentioning

confidence: 99%

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ATP Potentiates Agrin-induced AChR Aggregation in Cultured Myotubes

Siow¹,

Choi²,

Ting

et al. 2004

Journal of Biological Chemistry

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At vertebrate neuromuscular junctions, ATP is known to stabilize acetylcholine in the synaptic vesicles and to be co-released with it. We have shown previously that a nucleotide receptor, P2Y 1 receptor, is localized at the nmjs, and we propose that this mediates a trophic role for synaptic ATP there. In cultured myotubes, the activation of P2Y 1 receptors modulated agrin-induced acetylcholine receptor (

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“…Because UTP is known to activate small GTPases of the Rho family in different cell types (43)(44)(45)(46) and the EGFR activates Vav2, a guanine nucleotide exchange factor for RhoA and Rac1 (47), we next assessed whether the activated P2Y 2 R signals toward the EGFR and Rho family GTPases as part of its molecular mechanism. Pull-down assays using the RhoA and Rac1 substrate GST-rhoketin and GST-PAK, respectively (38,48), showed a significant 2-fold activation of RhoA and Rac1 in HCA perfused ex vivo with 1 M UTP.…”

Section: M␤cd Reduces the Utp-induced P2y 2 R Partitioning Into Membrmentioning

confidence: 99%

UTP Controls Cell Surface Distribution and Vasomotor Activity of the Human P2Y2 Receptor through an Epidermal Growth Factor Receptor-transregulated Mechanism

Norambuena

Palma

Poblete

et al. 2010

Journal of Biological Chemistry

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Extracellular nucleotides transmit signals into the cells through the P2 family of cell surface receptors. These receptors are amply expressed in human blood vessels and participate in vascular tone control; however, their signaling mechanisms remain unknown. Here we show that in smooth muscle cells of isolated human chorionic arteries, the activation of the P2Y 2 receptor (P2Y 2 R) induces not only its partition into membrane rafts but also its rapid internalization. Cholesterol depletion with methyl-␤-cyclodextrin reduced the association of the agonist-activated receptor into membrane rafts but did not affect either the UTPmediated vasoconstrictions or the vasomotor responses elicited by both serotonin and KCl. Ex vivo perfusion of human chorionic artery segments with 1-10 M UTP, a selective P2Y 2 R agonist, displaced the P2Y 2 R localization into membrane rafts within 1 min, a process preceded by the activation of both RhoA and Rac1 GTPases. AG1478, a selective and potent inhibitor of the epidermal growth factor receptor tyrosine kinase activity, not only blocked the UTP-induced vasomotor activity but also abrogated both RhoA and Rac1 activation, the P2Y 2 R association with membrane rafts, and its internalization. Altogether, these results show for the first time that the plasma membrane distribution of the P2Y 2 R is transregulated by the epidermal growth factor receptor, revealing an unsuspected functional interplay that controls both the membrane distribution and the vasomotor activity of the P2Y 2 R in intact human blood vessels.

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P2Y₁, P2Y₂, P2Y₄, and P2Y₆receptors are coupled to Rho and Rho kinase activation in vascular myocytes

Cited by 102 publications

References 31 publications

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

ATP Potentiates Agrin-induced AChR Aggregation in Cultured Myotubes

UTP Controls Cell Surface Distribution and Vasomotor Activity of the Human P2Y2 Receptor through an Epidermal Growth Factor Receptor-transregulated Mechanism

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