Involvement of multiple receptors in the actions of extracellular ATP: the example of vascular endothelial cells

doi:10.1016/1357-2725(94)00059-X

The International Journal of Biochemistry & Cell Biology

Volume 27, Issue 1, January 1995, Pages 1-7

https://doi.org/10.1016/1357-2725(94)00059-X Get rights and content

Abstract

The role of ATP and ADP as intercellular mediators is now well established. The presence of the nucleotides in extracellular fluids can result from several mechanisms: cell lysis, selective permeabilization of the plasma membrane and exocytosis of secretory vesicles, such as platelet dense bodies. Extracellular adenine nucleotides are rapidly degraded by ectonucleotidases expressed inter alia on the surface of endothelial cells. They act on cells via the family of P₂ receptors which encompasses more than 5 subtypes, some of which have been cloned recently. The P_2T, P_2U and P_2Y receptors belong to the superfamily of receptors coupled to G proteins, whereas the P_2X receptor is a cation channel and the P_2Z receptor a non-selective pore. ATP and ADP stimulate the endothelial production of prostacyclin (PGI₂) and nitric oxide (NO), two vasodilators and inhibitors of platelet aggregation, via an increase in cytosolic Ca²⁺. This action of adenine nucleotides is believed to limit the extent of intravascular platelet aggregation and to help localize thrombus formation to areas of endothelial damage. The endothelial response to nucleotides is mediated by at least two distinct subtypes of P₂ receptors, P_2Y and P_2U, both coupled to phospholipase C.

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This confirms that deformation of the human RBC is required to observe the effect of HU on ATP release. One fate of RBC-derived ATP is binding to purinergic receptors on the endothelial cell surface [28–31] where it stimulates production and subsequent release of NO from the endothelial cell. Through the use of the microfluidic device, the aforementioned path of RBC-derived ATP is mimicked, and NO produced from adhered bPAECs, as seen in Fig. 4, can be monitored.
Red blood cells (RBCs) release adenosine triphosphate (ATP) in response to a variety of stimuli, including flow-induced deformation. Hydroxyurea (HU), a proven therapy for individuals with sickle cell disease (SCD), is known to improve blood flow. However, the exact mechanism leading to the improved blood flow is incomplete. Here, we report that the incubation of human RBCs with HU enhances ATP release from these cells and that this ATP is capable of stimulating nitric oxide (NO) production in an endothelium. RBCs incubated with HU were pumped through micron-size flow channels in a microfluidic device. The release of ATP from the RBCs was measured using the luciferin–luciferase assay in detection wells on the device that were separated from the flow channels by a porous polycarbonate membrane. NO released from a layer of bovine artery endothelial cells (bPAECs) cultured on the polycarbonate membrane was also measured using the extracellular NO probe DAF-FM. ATP release from human RBCs incubated with 100 μM HU was observed to be 2.06 ± 0.37-fold larger than control samples without HU (p < 0.05, N ⩾ 3). When HU-incubated RBCs were flowed under a layer of bPAECs, NO released from the bPAEC layer was measured to be 1.34 ± 0.10-fold higher than controls. An antagonist of the P2Y receptor established that this extra 30% increase in NO release is ATP mediated. Furthermore, when RBCs were incubated with L-NAME, a significant decrease in endothelium-derived NO production was observed. Control experiments suggest that RBC-generated NO indirectly affects endothelial NO production via its effects on RBC-derived ATP release.
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MinireviewInvolvement of multiple receptors in the actions of extracellular ATP: the example of vascular endothelial cells

Abstract

TIPS

TIPS

Gen. Pharmac.

J. biol. Chem.

FEBS Lett.

Biochem. biophys. Acta

Eur. J. Pharmac.

TIPS

Eur. J. Pharmac.

FEBS Lett.

The multidrug resistance (mdrl) gene product functions as an ATP channel

Comparison of P2-purinergic receptors of aortic endothelial cells with those of adrenal medulla: evidence for heterogeneity of receptor subtype and of inositol phosphate response

Molec. Pharmac.

Role of cyclic AMP in promoting the thromboresistance of human endothelial cells by enhancing thrombomodulin and decreasing tissue factor activities

Br. J. Pharmac.

Identification of a P2Y-purinergic receptor that inhibits adenylyl cyclase

J. Pharmac. exp. Ther.

A basis for distinguishing two types of purinergic receptors

A dual function for adenosine 5′-triphosphate in the regulation of vascular tone

Circ. Res.

Regulation of P2Y-purinoceptor-mediated prostacyclin release from human endothelial cells by cytoplasmic calcium concentration

Br. J. Pharmac.

New Roles for G-protein βγ dimers in transmembrane signalling

Nature

Enhancement of endothelial cyclic AMP accumulation by adenine nucleotides: role of methylxanthine-sensitive sites

Am. J. Physiol.

Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides

Am. J. Physiol.

Functional expression and photoaffinity labeling of a cloned P2U purinergic receptor

Expression of a cloned P2Y purinergic receptor that couples to phospholipase C

Molec. Pharmac.

Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation

N. Engl. J. Med.

Minireview
Involvement of multiple receptors in the actions of extracellular ATP: the example of vascular endothelial cells

Comparison of P₂-purinergic receptors of aortic endothelial cells with those of adrenal medulla: evidence for heterogeneity of receptor subtype and of inositol phosphate response

Identification of a P_2Y-purinergic receptor that inhibits adenylyl cyclase

Regulation of P_2Y-purinoceptor-mediated prostacyclin release from human endothelial cells by cytoplasmic calcium concentration

Signal transduction via P₂-purinergic receptors for extracellular ATP and other nucleotides

Functional expression and photoaffinity labeling of a cloned P_2U purinergic receptor

Expression of a cloned P_2Y purinergic receptor that couples to phospholipase C