Deformation-induced ATP release from red blood cells requires CFTR activity

Sprague, Randy S.; Ellsworth, Mary L.; Stephenson, Alan H.; Kleinhenz, Mary Ellen; Lonigro, Andrew J.

doi:10.1152/ajpheart.1998.275.5.h1726

Cited by 245 publications

(381 citation statements)

References 21 publications

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“…Erythrocytes from various species, including human, release ATP and take up dye in a low-oxygen environment, when mechanically stressed, or when depolarized with a high concentration of potassium gluconate (6,32,50). Figure 6 shows that the osmotic stress-induced uptake of YoPro from the extracellular space by frog erythrocytes was inhibited by probenecid.…”

Section: Resultsmentioning

confidence: 99%

Probenecid, a gout remedy, inhibits pannexin 1 channels

Silverman¹,

Locovei

Dahl

2008

American Journal of Physiology-Cell Physiology

371

376

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Probenecid is a well-established drug for the treatment of gout and is thought to act on an organic anion transporter, thereby affecting uric acid excretion in the kidney by blocking urate reuptake. Probenecid also has been shown to affect ATP release, leading to the suggestion that ATP release involves an organic anion transporter. Other pharmacological evidence and the observation of dye uptake, however, suggest that the nonvesicular release of ATP is mediated by large membrane channels, with pannexin 1 being a prominent candidate. In the present study we show that probenecid inhibited currents mediated by pannexin 1 channels in the same concentration range as observed for inhibition of transport processes. Probenecid did not affect channels formed by connexins. Thus probenecid allows for discrimination between channels formed by connexins and pannexins.connexin; transport; erythrocyte; ATP release PROBENECID HAS BEEN USED for decades for the treatment of gout. The mechanism of action of the drug is inhibition of a renal tubular transporter, thereby facilitating the excretion of the disease causative uric acid by blocking reuptake (5, 26, 37). Probenecid-sensitive transporters are widespread and are even found in plants (30,31,44,52,56). The inhibition of the transporter by probenecid is also exploited clinically to increase the effective concentrations of antibiotics, chemotherapeutics, and other medications.The inhibitory effect of probenecid on organic anion transporters is well established, and the effect is thought to be so specific that the drug is often used as a diagnostic tool, i.e., its effect is typically interpreted as an involvement of an anion transporter in the tested parameter. Accordingly, block of cAMP or cGMP release from erythrocytes (18, 25), ATP release from glia cells (1, 17), and block of dye loss in various cell types (20,21,23) by probenecid have been presented as evidence for a role of transporters in these phenomena. However, alternative pathways for the transit of these molecules across the plasma membrane have to be considered. Besides the well-documented vesicular release of ATP, a parallel release through membrane channels must exist, because the release is attenuated by drugs that do not interfere with vesicular release but affect gap junction proteins and because ATP release in several cell types is associated with uptake of dye from the extracellular medium (13).Special attention has to be given to pannexin 1 as an ATP release channel because of the specific properties of pannexin 1 channels and because of the expression pattern of pannexin 1 (2, 16, 28, 32-34, 55, 59). Pannexin 1 channels are highly permeable to ATP and to dyes typically used for dye flux measurements through gap junction channels. These dyes are in the same size range as the Ca 2ϩ indicator dyes whose loss is attenuated by probenecid. Pannexin 1 channels also are mechanosensitive, consistent with a role in Ca 2ϩ wave initiation. Expression of pannexin 1 is found in cells exhibiting ATP release, including er...

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Section: Resultsmentioning

confidence: 99%

Probenecid, a gout remedy, inhibits pannexin 1 channels

Silverman¹,

Locovei

Dahl

2008

American Journal of Physiology-Cell Physiology

371

376

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“…However, this issue continues to be controversial. Glutamate-stimulated ATP release from microglia cells is significantly attenuated in cells isolated from CFTR knockout mice [82] and erythrocytes isolated from CF patients are reported to show no mechanical-induced ATP release [83]. Thus, a final verdict on this issue is premature.…”

Section: The Link To Cftrmentioning

confidence: 99%

ATP release from non-excitable cells

Praetorius

Leipziger

2009

Purinergic Signalling

205

229

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All cells release nucleotides and are in one way or another involved in local autocrine and paracrine regulation of organ function via stimulation of purinergic receptors. Significant technical advances have been made in recent years to quantify more precisely resting and stimulated adenosine triphosphate (ATP) concentrations in close proximity to the plasma membrane. These technical advances are reviewed here. However, the mechanisms by which cells release ATP continue to be enigmatic. The current state of knowledge on different suggested mechanisms is also reviewed. Current evidence suggests that two separate regulated modes of ATP release co-exist in nonexcitable cells: (1) a conductive pore which in several systems has been found to be the channel pannexin 1 and (2) vesicular release. Modes of stimulation of ATP release are reviewed and indicate that both subtle mechanical stimulation and agonist-triggered release play pivotal roles. The mechano-sensor for ATP release is not yet defined.

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“…This is potentially very important because it is known that some patient groups known to have low NO production or complications involving blood flow are also known to have RBCs that release lower than normal amounts of ATP upon pharmacological activation or physical deformation of the erythrocyte. Patients with primary pulmonary hypertension, 12 cystic fibrosis, 13 and diabetes 14,15 are example patient groups with these lower ATP release values. Figure 1 demonstrate that platelet NO can be measured via fluorescence spectrophotometry in tubing having a diameter that approximates an arteriole in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…For example, patients with pulmonary hypertension 12 and cystic fibrosis 13 release less RBC-derived ATP upon mechanical deformation than the RBCs from healthy controls. Recently, in a separate study, it was reported that patients with type II diabetes mellitus released 91 ( 10 nM ATP versus 190 ( 10 nM ATP release in control RBCs.…”

Section: Discussionmentioning

confidence: 99%

Red Blood Cell Stimulation of Platelet Nitric Oxide Production Indicated by Quantitative Monitoring of the Communication between Cells in the Bloodstream

Carroll

Karunarathne

et al. 2007

Anal. Chem.

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ATP is a recognized stimulus of nitric oxide synthase and is released from red blood cells (RBCs) upon deformation. The objective of this work is to demonstrate that RBCs stimulate nitric oxide production in platelets by employing a continuous flow analysis system in which the stream contains both RBCs and platelets. Here, two drugs known to improve blood flow in vivo (pentoxyfilline and iloprost) are shown to increase both the release of RBC-derived ATP and the production of platelet-derived NO. A flowbased chemiluminescence assay (in vitro) was employed to quantitatively determine the amount of ATP released from erythrocytes subjected to flow-induced deformation. Prior to being subjected to flow, erythrocytes were incubated in the absence or presence of 4.8 µM pentoxyfilline or 80 nM iloprost. Erythrocytes obtained from rabbits (n ) 22) that were subjected to flow released 239 ( 29 nM ATP. When treated with pentoxyfilline, the ATP released from the flowing RBCs increased to 450 ( 94 nM ATP. An increase in RBC-derived ATP was also measured for iloprost-incubated RBCs in flow (362 ( 45 nM ATP). Importantly, platelets that were loaded with diaminofluorofluorescein diacetate, an intracellular fluorescence probe for NO, exhibited increases in fluorescence intensity by 16% in the presence of RBCs treated with pentoxyfilline and a 10% increase when treated with iloprost. When the ATP release from the RBCs was inhibited with glybenclamide, the platelet fluorescence intensity decreased by 25 and 51% for RBCs incubated with pentoxyfilline and iloprost, respectively. In an experiment not involving the RBC, inhibition of the P2x receptor on the platelets (an ATP receptor) resulted in no increase in platelet NO production, suggesting that the NO production in the activated platelet is due to ATP.In addition to its well-known ability as a vasodilator, NO is also able to inhibit platelet activation and aggregation. Platelets have also been shown to produce NO upon activation. 1 Freedman et al. simultaneously measured NO production and aggregation of platelets upon activation with ATP. 2 These authors placed an electrode for NO into the cell of an aggregometer in order to simultaneously monitor the NO release from platelets and the aggregation of the platelets, thus demonstrating that NO was produced and released by these cells upon activation. From these studies, the authors concluded that NO released by the platelets was key to preventing further platelet recruitment to the activated platelets, but only mildly prevented their adhesion to an endothelium.In question concerning the production and release of plateletderived NO is the mechanism by which the NO production is stimulated. For example, ATP is a recognized stimulus of nitric oxide synthase (NOS) and subsequent production of platelet NO; moreover, it is also known that ATP is released from platelets upon activation. 3 However, it has not been established if ATP released from activated platelets has the ability to stimulate the production of NO in platelets. Here, res...

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Deformation-induced ATP release from red blood cells requires CFTR activity

Cited by 245 publications

References 21 publications

Probenecid, a gout remedy, inhibits pannexin 1 channels

Probenecid, a gout remedy, inhibits pannexin 1 channels

ATP release from non-excitable cells

Red Blood Cell Stimulation of Platelet Nitric Oxide Production Indicated by Quantitative Monitoring of the Communication between Cells in the Bloodstream

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