scholarly journals The P2Y receptors and thrombosis

2013 ◽  
Vol 2 (6) ◽  
pp. 241-253 ◽  
Author(s):  
Christian Gachet ◽  
Béatrice Hechler
Keyword(s):  
P2y Receptors

ATP potently modulates anion channel-mediated excitatory amino acid release from cultured astrocytes

2002 ◽  
Vol 283 (2) ◽  
pp. C569-C578 ◽  
Author(s):  
Alexander A. Mongin ◽  
Harold K. Kimelberg
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Atp Release ◽  
Anion Channel ◽  
P2y Receptors ◽  
Cell Swelling ◽  
Channel Blockers ◽  
Medium Osmolarity ◽  
Subsequent Activation

Volume-dependent ATP release and subsequent activation of purinergic P2Y receptors have been implicated as an autocrine mechanism triggering activation of volume-regulated anion channels (VRACs) in hepatoma cells. In the brain ATP is released by both neurons and astrocytes and participates in intercellular communication. We explored whether ATP triggers or modulates the release of excitatory amino acid (EAAs) via VRACs in astrocytes in primary culture. Under basal conditions exogenous ATP (10 μM) activated a small EAA release in 70–80% of the cultures tested. In both moderately (5% reduction of medium osmolarity) and substantially (35% reduction of medium osmolarity) swollen astrocytes, exogenous ATP greatly potentiated EAA release. The effects of ATP were mimicked by P2Y agonists and eliminated by P2Y antagonists or the ATP scavenger apyrase. In contrast, the same pharmacological maneuvers did not inhibit volume-dependent EAA release in the absence of exogenous ATP, ruling out a requirement of autocrine ATP release for VRAC activation. The ATP effect in nonswollen and moderately swollen cells was eliminated by a 5–10% increase in medium osmolarity or by anion channel blockers but was insensitive to tetanus toxin pretreatment, further supporting VRAC involvement. Our data suggest that in astrocytes ATP does not trigger EAA release itself but acts synergistically with cell swelling. Moderate cell swelling and ATP may serve as two cooperative signals in bidirectional neuron-astrocyte communication in vivo.

Overview of the pharmacology and physiological roles of P2Y receptors

2012 ◽  
Vol 1 (5) ◽  
pp. 581-588 ◽  
Author(s):  
Jean-Marie Boeynaems ◽  
Didier Communi ◽  
Bernard Robaye
Keyword(s):  
P2y Receptors

scholarly journals Pregnancy-enhanced Ca2+ responses to ATP in uterine artery endothelial cells is due to greater capacitative Ca2+ entry rather than altered receptor coupling

2006 ◽  
Vol 190 (2) ◽  
pp. 373-384 ◽  
Author(s):  
Shannon M Gifford ◽  
Fu-Xian Yi ◽  
Ian M Bird
Keyword(s):  
Endothelial Cells ◽  
Uterine Artery ◽  
Purinergic Receptor ◽  
Cell Types ◽  
P2y Receptors ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Initial Transient ◽  
Receptor Coupling ◽  
Specific Variation

Uterine artery endothelial cells (UAEC) derived from pregnant (P-UAEC) and nonpregnant (NP-UAEC) ewes retain pregnancy-specific differences in cell signaling as well as vasodilator production through passage 4. In particular, when P- and NP-UAEC are stimulated with ATP over a 2.5 min recording period, they exhibit similar initial transient peaks in the intracellular free Ca2+ concentration ([Ca2+]i), but the P-UAEC show a heightened sustained phase. In order to establish whether thiswas due to an altered subclass of purinergic receptor (P2), both the dose dependencyof [Ca2+]i responses to ADP and UTP and the profile of purinergic receptor expression are determined in NP- and P-UAEC. Our findings indicate that while several isoforms of P2X and P2Y receptors are present, it is P2Y2 that is responsible for the ATP-induced initial transient peak in both cell types. We also characterized several key components of the ATP-induced Ca2+ signaling cascade, including the inositol 1,4,5-trisphosphate receptor and G-proteins, but could not confirm any pregnancy-specific variation in the protein expression that correlated with pregnancy-specific differences in prolonged Ca2+ signaling. We thus investigated whether such a difference may be inherent to the cell itself rather than specific to the purinergic receptor-signaling pathway. Using thapsigargin (Tg), we were able to demonstrate that the initial Tg-sensitive intracellular pool of Ca2+is nearly identical with the capacity in both cell types, but the P-UAEC is nonetheless capable of greater capacitative Ca2+ entry (CCE) than NP-UAEC. Furthermore, CCE induced by Tg could be dramatically inhibited by 2-aminoethoxydiphenyl borate, suggesting a role for store-operated channels in the ATP-induced [Ca2+]i response. We conclude that changes at the level of capacitative entry mechanisms rather than switching of receptor subtype or coupling to phospholipase C underlies pregnancy adaptation of UAEC at the level of Ca2+signaling.

Antagonism of endogenous putative P2Y receptors reduces the growth of MDCK-derived cysts cultured in vitro

2007 ◽  
Vol 292 (1) ◽  
pp. F15-F25 ◽  
Author(s):  
Clare M. Turner ◽  
Brian F. King ◽  
Kaila S. Srai ◽  
Robert J. Unwin
Keyword(s):  
Therapeutic Potential ◽  
Cyst Formation ◽  
P2y Receptors ◽  
P2x Receptor ◽  
P2y Receptor ◽  
Cyst Size ◽  
Reactive Blue 2 ◽  
Cyst Growth

P2Y receptors couple to G proteins and either mobilize intracellular Ca2+ or alter cAMP levels to modulate the activity of Ca2+- and cAMP-sensitive ion channels. We hypothesize that increased ion transport into the lumen of MDCK cysts can osmotically drive fluid movement and increase cyst size. Furthermore, activation of the adenylate cyclase/cAMP pathway may trigger cell proliferation via an extracellular signal-related kinase cascade. To test this hypothesis, several P2Y receptor inhibitors were used on the MDCK in vitro model of renal cyst formation. The nonspecific P2 receptor inhibitors reactive blue 2 and suramin reduced cyst growth significantly, as did PPADS and, to a lesser extent, the P2Y1-specific antagonist MRS2179. Cyst growth was reduced by ∼50% when ATP was removed from the culture medium with apyrase, although stable analogs of ATP failed to increase cyst size. The nonselective P2X receptor inhibitor Coomassie brilliant blue G was ineffective at reducing cyst growth, suggesting no involvement of P2X receptors. Finally, the presence of selective inhibitors of ERK activation (either PD98059 or U0126) greatly reduced cyst growth, whereas in untreated cysts ERK activity was observed to increase with time. We conclude that stimulation of endogenous P2Y receptors by extracellular ATP increases growth of MDCK cysts via cAMP-dependent activation of the ERK pathway. P2Y receptor antagonists may have therapeutic potential in reducing cyst size and slowing disease progression; although further studies in vitro and in vivo are needed to investigate the specificity and role of these P2Y receptors in renal cystic diseases.

scholarly journals John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors

2015 ◽  
Vol 13 ◽  
pp. 286-298 ◽  
Author(s):  
Kenneth A. Jacobson ◽  
Zhan-Guo Gao ◽  
Silvia Paoletta ◽  
Evgeny Kiselev ◽  
Saibal Chakraborty ◽  
...  
Keyword(s):  
Drug Design ◽  
P2y Receptors

scholarly journals Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization

2007 ◽  
Vol 151 (2) ◽  
pp. 226-236 ◽  
Author(s):  
Z Gerevich ◽  
Z Zadori ◽  
C Müller ◽  
K Wirkner ◽  
W Schröder ◽  
...  
Keyword(s):  
G Protein ◽  
P2y Receptors ◽  
P2x3 Receptor

scholarly journals Studies of the interaction of ticagrelor with the P2Y13 receptor and with P2Y13-dependent pro-platelet formation by human megakaryocytes

2016 ◽  
Vol 116 (12) ◽  
pp. 1079-1088 ◽  
Author(s):  
Anna Björquist ◽  
Christian A. Di Buduo ◽  
Eti A. Femia ◽  
Robert F. Storey ◽  
Richard C. Becker ◽  
...  
Keyword(s):  
Platelet Count ◽  
Cellular Response ◽  
P2y Receptors ◽  
Cell System ◽  
Experimental Models ◽  
Significant Activity ◽  
Label Free ◽  
Coronary Syndrome ◽  
Platelet Formation

SummaryTicagrelor is an antagonist of the platelet P2Y12 receptor for ADP, approved for the prevention of thromboembolic events in patients with acute coronary syndrome. Previous studies showed that ticagrelor has no significant activity versus P1 receptors for adenosine and other known P2Y receptors, with the exception of P2Y13, which was not tested. The P2Y12 antagonist cangrelor has been shown to also inhibit P2Y13 and to decrease the P2Y13-regulated capacity of megakaryocytes to produce pro-platelets. We tested whether or not ticagrelor inhibits P2Y13 signalling and function. The in vitro effects of ticagrelor, its active (TAM) and inactive (TIM) metabolites, cangrelor and the P2Y13 antagonist MRS2211 were tested in two experimental models: 1) a label-free cellular response assay in P2Y13-transfected HEK293 T-REx cells; and 2) pro-platelet formation by human megakaryocytes in culture. Ticagrelor, TAM, cangrelor and MRS2211, but not TIM, inhibited the cellular responses in P2Y13-transfected cells. In contrast, only MRS2211 and cangrelor, confirming previous results, inhibited pro-platelet formation by megakaryocytes in vitro. The platelet count of patients randomised to treatment with ticagrelor in the PLATO trial did not change during treatment and was comparable to those of patients randomised to clopidogrel. In conclusion, ticagrelor and TAM act as P2Y13 antagonists in a transfected cell system in vitro but this does not translate into any impact on pro-platelet formation in vitro or altered platelet count in patients.

Varicosity-Schwann Cell Interactions Mediated by ATP in the Mouse Vas Deferens

2005 ◽  
Vol 93 (5) ◽  
pp. 2787-2796 ◽  
Author(s):  
Y. Q. Lin ◽  
M. R. Bennett
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Vas Deferens ◽  
P2y Receptors ◽  
Autonomic Nerve ◽  
Nerve Terminals ◽  
Metabotropic Receptors ◽  
Mouse Vas Deferens ◽  
Endogenous Release ◽  
Autonomic Nerve Terminals

Schwann cells, from a variety of sources, are known to possess P2Y purinergic metabotropic receptors. However, it is not known if Schwann cells associated with autonomic nerve terminals possess such receptors and if so whether these receptors are activated by the endogenous release of ATP from the nerve terminals. We show that such Schwann cells in the vas deferens give evoked calcium transients on nerve stimulation. These transients are mediated, at least in part, by the endogenous release of ATP, which acts on Schwann cell P2Y receptors to release calcium from within the cells. This work suggests the possibility that Schwann cells are active participants in the process of junctional transmission in the autonomic nervous system.

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