Mechanisms by which extracellular ATP and UTP stimulate the release of prostacyclin from bovine pulmonary artery endothelial cells

Lustig, Kevin D.; Erb, Laurie; Landis, David M.; Hicks-Taylor, Cathy S.; Zhang, Xiaoke; Sportiello, Michael G.; Weisman, Gary A.

doi:10.1016/0167-4889(92)90028-a

Cited by 70 publications

(52 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of the P2Y 2 receptor has been reported to increase prostacyclin and nitric oxide release from endothelial cells (31,32). Studies have shown that nitric oxide modulates the level of VCAM-1 protein expression in endothelial cells (33).…”

Section: Discussionmentioning

confidence: 99%

The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells

Seye

Jain

et al. 2003

Journal of Biological Chemistry

Self Cite

108

114

View full text Add to dashboard Cite

Extracellular nucleotides cause a wide range of cellular responses and appear to play a role in the regulation of many vascular functions (1, 2). Vascular cells release nucleotides when exposed to stimuli such as ischemia, hypoxia, and chemical or mechanical stress (3, 4). It also is becoming apparent that extracellular nucleotides can promote the development of a variety of pathologies including disorders of the immune system, and neurodegenerative and vascular diseases (1). Indeed, ATP or UTP induces proliferation and migration of vascular smooth muscle cells, two processes involved in the development of intimal lesions found in atherosclerosis and post-angioplasty restenosis. The biological effects of extracellular nucleotides are mediated through activation of P1 and P2 purinergic receptors. P1 receptors are responsive to adenosine, whereas P2 receptors are activated by a variety of nucleotides including ATP and UTP (5, 6). The P2 receptors are subdivided into two distinct categories, the metabotropic Gprotein-coupled (P2Y) receptors and the ionotropic ligandgated channel (P2X) receptors (6, 7). Vascular cells have been shown to express metabotropic P2Y and ionotropic P2X receptors (5, 8). It has been reported that P2Y 2 receptors are upregulated in cells of rat intimal lesions following balloon angioplasty (9). Our recent studies showed that placement of a silicone collar around the rabbit carotid artery promoted upregulation of P2Y 2 receptors in vascular smooth muscle cells and endothelium (10). Subsequently, local infusion of UTP was shown to stimulate intimal hyperplasia and increase intimal monocyte infiltration (10), suggesting a role for P2Y 2 receptors in the recruitment of blood monocytes leading to inflammation in atherosclerosis.Monocyte recruitment into the vessel wall is a complex process that includes cell rolling, firm attachment, and directed migration. It is now becoming evident that adhesion molecules such as VCAM-1 play an important role in leukocyte adherence to vascular endothelial cells (11,12). VCAM-1 expression is induced or up-regulated by proinflammatory cytokines such as TNF-␣ 1 and interleukin 1-␤ on cellular components of the arterial wall including endothelial cells, smooth muscle cells, and fibroblasts (13-15). ATP and UTP have been shown to induce cell-cell adhesion in a monocyte/macrophage lineage and neutrophil adherence to an endothelial cell monolayer (16,17), raising the possibility that released ATP and UTP could induce endothelial cell activation by an autocrine/paracrine mechanism to regulate leukocyte adherence.

show abstract

Section: Discussionmentioning

confidence: 99%

The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells

Seye

Jain

et al. 2003

Journal of Biological Chemistry

Self Cite

108

114

View full text Add to dashboard Cite

show abstract

“…Responses to extracellular nucleotides are mediated by P2 receptors that belong to two receptor superfamilies: P2Y G protein-coupled receptors (GPCRs) 1 and P2X ligand-gated ion channels. Multiple P2Y subtypes have been classified pharmacologically and molecularly and are predominantly linked to activation of phospholipase C and increased levels of inositol 1,4,5-trisphosphate and diacylglycerol, leading to elevations in the intracellular free calcium concentration ([Ca 2ϩ ] i ) and the activation of protein kinase C (PKC) (1)(2)(3)(4).…”

mentioning

confidence: 99%

Structural Basis of Agonist-induced Desensitization and Sequestration of the P2Y2 Nucleotide Receptor

Garrad¹,

Otero²,

Erb³

et al. 1998

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Molecular determinants of P2Y 2 receptor desensitization and sequestration have been investigated. Wildtype P2Y 2 receptors and a series of five C-terminal truncation mutants of the receptor were epitope-tagged and stably expressed in 1321N1 cells. These constructs were used to assess the importance of the intracellular C terminus on 1) UTP-stimulated increases in intracellular calcium concentration, 2) homologous desensitization of the receptor, and 3) agonist-induced decreases in cellsurface density (receptor sequestration) of epitopetagged receptors using fluorescence-activated cell sorting. The potency and efficacy of UTP were similar for the wild-type and all mutant P2Y 2 receptors. Truncation of 18 or more amino acids from the C terminus increased by ϳ30-fold the concentration of UTP necessary to desensitize the receptor. Both the rate and magnitude of UTP-induced receptor sequestration were decreased with progressively larger truncations of the C terminus. Furthermore, the recovery from sequestration was slower for the most extensively truncated receptor. Complete desensitization was obtained with >50% of the original receptor complement remaining on the cell surface. Protein kinase C activation, which desensitizes the P2Y 2 receptor, had no effect on sequestration, consistent with the ideas that desensitization and sequestration are discrete events and that agonist occupancy is required for receptor sequestration.Responses to extracellular nucleotides are mediated by P2 receptors that belong to two receptor superfamilies: P2Y G protein-coupled receptors (GPCRs) 1 and P2X ligand-gated ion channels. Multiple P2Y subtypes have been classified pharmacologically and molecularly and are predominantly linked to activation of phospholipase C and increased levels of inositol 1,4,5-trisphosphate and diacylglycerol, leading to elevations in the intracellular free calcium concentration ([Ca 2ϩ ] i ) and the activation of protein kinase C (PKC) (1-4). The P2Y 2 nucleotide receptor subtype (formerly the P 2U receptor) is distinguished pharmacologically from the other known mammalian P2Y receptor subtypes by the equal potency and efficacy of the naturally occurring agonists ATP and UTP.Activation of P2Y 2 receptors present in airway epithelium increases Cl Ϫ secretion through Ca 2ϩ -dependent and outwardly rectifying Cl Ϫ channels (5). It has been shown that P2Y 2 receptor activation by UTP in airway epithelia of cystic fibrosis patients can increase Cl Ϫ secretion, thereby effectively bypassing the defective cAMP-dependent Cl Ϫ transport (6). Like other members of the GPCR superfamily, P2Y 2 receptors undergo agonist-induced desensitization (7), but little is known about the mechanisms involved in desensitization of the P2Y 2 receptor. It seems likely that a fuller understanding of desensitization and the signaling pathways that affect the P2Y 2 receptor may lead to improved therapies targeted to this receptor.Desensitization of GPCRs is a complex process involving phosphorylation of the receptors by multiple pro...

show abstract

“…P2YRs have been shown to be coupled either directly or indirectly to G q , G i , G o , and G 12 protein activation and downstream signaling pathways associated with alterations in PLC or adenylyl cyclase activities [1,20,[69][70][71]. The agonist selectivity of P2YR subtypes varies widely, in contrast to P2X receptors [1]; for example, the P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 14 receptor subtypes can be activated by uridine nucleotides or UDP-glucose that are ineffective agonists of all P2X and four P2Y receptor subtypes [1,4,19,20,56,70,[72][73][74].…”

Section: P2 Receptors In the Cnsmentioning

confidence: 99%

“…Activation of the G q -coupled P2Y 2 R by ATP or UTP (EC 50 ∼1-6 μM) [7,74] is linked to the stimulation of PLC leading to an increase in the production of inositol 1,4,5 trisphosphate (IP 3 ) and diacylglycerol that elevates the intracellular Ca 2+ concentration, [Ca 2+ ] i , and activates protein kinase C (PKC), respectively [73,87]. Recent studies have demonstrated that the P2Y 2 R can activate signaling pathways independent of coupling to G q protein.…”

Section: P2y 2 Receptor Signaling Pathwaysmentioning

confidence: 99%

“…We also hypothesize that endothelial P2Y 2 R relocation to adherens junctions assists in the transient disruption of endothelial junctions and escorts leukocytes to endothelial borders for paracellular diapedesis, possibly through association of the P2Y 2 R with the α V β 3 integrin. This integrin is known to form a complex with the P2Y 2 R [23] and with JAM-1 [276], a junctional adhesion molecule in endothelial cells that interacts with the leukocyte integrin, LFA-1, and is important for both leukocyte adhesion and diapedesis [277] activation [73]; and the upregulation of tissue factor, an initiator of platelet aggregation [260]. Recently, we found that activation of the P2Y 2 R in human coronary artery endothelial cells causes a rapid translocation of the receptor to cell-cell junctional zones where it interacts with VEcadherin (unpublished results), a protein found specifically in endothelial adherens junctions that is important for maintaining the vascular permeability barrier.…”

Section: Proinflammatory P2y 2 R Functions In Endotheliummentioning

confidence: 99%

See 1 more Smart Citation

Neuroprotective roles of the P2Y2 receptor

Weisman

Ajit

Garrad

et al. 2012

Purinergic Signalling

Self Cite

View full text Add to dashboard Cite

Mechanisms by which extracellular ATP and UTP stimulate the release of prostacyclin from bovine pulmonary artery endothelial cells

Cited by 70 publications

References 57 publications

The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells

The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells

Structural Basis of Agonist-induced Desensitization and Sequestration of the P2Y2 Nucleotide Receptor

Neuroprotective roles of the P2Y2 receptor

Contact Info

Product

Resources

About