Role of Pannexin-1 hemichannels and purinergic receptors in the pathogenesis of human diseases

Velasquez, Stephani; Eugenín, Eliseo A.

doi:10.3389/fphys.2014.00096

Cited by 75 publications

(83 citation statements)

References 155 publications

(200 reference statements)

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“…An emerging literature demonstrates the importance of extracellular ATP purinergic signaling in viral infections, specifically, those caused by HIV-1 (21,22,(31)(32)(33). While limited data on other enveloped viruses exist, it is reported that internalization of pseudotyped HIV was not reduced by purinergic inhibitors (12).…”

Section: Discussionmentioning

confidence: 99%

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Swartz

Esposito

Durham

et al. 2014

J Virol

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Human immunodeficiency virus type 1 (HIV-1) infection is chronic and presently still incurable. Antiretroviral drugs effectively suppress replication; however, persistent activation of inflammatory pathways remains a key cause of morbidity. Recent studies proposed that purinergic signaling is required for HIV-1 infection. Purinergic receptors are distributed throughout a wide variety of tissue types and detect extracellular ATP as a danger signal released from dying cells. We have explored how these pathways are involved in the transmission of HIV-1 from cell to cell through virological synapses. Infection of CD4 ؉ T lymphocytes with HIV-1 in the presence of an inhibitor of P2X receptors effectively inhibited HIV-1 infection through both cell-free and cellto-cell contact in a dose-dependent manner. Inhibition of direct cell-to-cell infection did not affect the formation of virological synapses or the subsequent cell-to-cell transfer of HIV-1. During both cell-free and cell-to-cell CD4 ؉ T lymphocyte infection, purinergic antagonists blocked infection at the level of viral membrane fusion. During cell-to-cell transmission, we observed CXCR4 colocalization with the newly internalized virus particles within target lymphocytes and found that the purinergic antagonists did not impair the recruitment of the coreceptor CXCR4 to the site of Gag internalization in the target cell. In a screen of a library of purinergic antagonists, we found that the most potent inhibitors of HIV-1 fusion were those that target P2X receptors, while P2Y-selective receptor antagonists or adenosine receptor antagonists were ineffective. Our results suggest that P2X receptors may provide a therapeutic target and that purinergic antagonists may have potent activity against viral infection of CD4 ؉ T lymphocytes by both cell-free and cell-to-cell transmission. IMPORTANCEThis study identifies purinergic antagonists to be potent inhibitors of HIV-1 cell-free and cell-to-cell-mediated infection and provides a stepwise determination of when these compounds inhibit HIV-1 infection. These data provide a rationale for the development of novel antiretroviral therapies that have a dual role in both direct antiviral activity and the reduction of HIV-associated inflammation. Purinergic antagonists are shown here to have equivalent efficacy in inhibiting HIV infection via cell-free and cell-to-cell infection, and it is shown that purinergic receptors could provide an attractive therapeutic anti-HIV target that might avoid resistance by targeting a host signaling pathway that potently regulates HIV infection. The high-throughput screen of HIV-1 fusion inhibitors further defines P2X-selective compounds among the purinergic compounds as being the most potent HIV entry inhibitors. Clinical studies on these drugs for other inflammatory indications suggest that they are safe, and thus, if developed for use as anti-HIV agents, they could reduce both HIV replication and HIV-related inflammation.

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Section: Discussionmentioning

confidence: 99%

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Swartz

Esposito

Durham

et al. 2014

J Virol

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“…This may also explain why anion channels have previously received much less attention than cation channels. It is worth noting that anion channels have been associated with cystic fibrosis, bleeding phenotypes, and inflammatory conditions [12, 13, 15, 26, 27] and may represent valuable therapeutic targets, as demonstrated by clinical use of CFTR modulators [28]. Further work will be required to investigate the contribution(s) by the cohort of platelet anion channels during platelet activation.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, pannexin-1 channels have been shown to amplify platelet activation responses to threshold agonist concentrations [14]. These ATP-permeable channels are associated with inflammatory conditions and may contribute to atherosclerosis [15]. …”

Section: Introductionmentioning

confidence: 99%

Extracellular chloride is required for efficient platelet aggregation

et al. 2017

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Anion channels perform a diverse range of functions and have been implicated in ATP release, volume regulation, and phosphatidylserine exposure. Platelets have been shown to express several anion channels but their function is incompletely understood. Due to a paucity of specific pharmacological blockers, we investigated the effect of extracellular chloride substitution on platelet activation using aggregometry and flow cytometry. In the absence of extracellular chloride, we observed a modest reduction of the maximum aggregation response to thrombin or collagen-related peptide. However, the rate of aggregation was substantially reduced in a manner that was dependent on the extracellular chloride concentration and aggregation in the absence of chloride was noticeably biphasic, indicative of impaired secondary signaling. This was further investigated by targeting secondary agonists with aspirin and apyrase or by blockade of the ADP receptor P2Y12. Under these conditions, the rates of aggregation were comparable to those recorded in the absence of extracellular chloride. Finally, we assessed platelet granule release by flow cytometry and report a chloride-dependent element of alpha, but not dense, granule secretion. Taken together these data support a role for anion channels in the efficient induction of platelet activation, likely via enhancement of secondary signaling pathways.

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“…Therefore, increased proliferation of fibroblasts plays a crucial role in atherosclerotic lesion progression and eventual rupture. This evidence indicates that Pannexin-1 channels, ATP, and P2 receptors are involved in fibroblast proliferation and plaque destabilization [84].…”

Section: Pannexin-1 Channels and Cardiac Fibrosismentioning

confidence: 99%

Pannexin-1 channels and their emerging functions in cardiovascular diseases

et al. 2015

ABBS

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Pannexin-1, Pannexin-2, and Pannexin-3 are three members of the Pannexin family of channel-forming glycoprotein. Their primary function is defined by their ability to form single-membrane channels. Pannexin-1 ubiquitously exists in many cells and organs throughout the body and is specially distributed in the circulatory system, while the expressions of Pannexin-2 and Pannexin-3 are mostly restricted to organs and tissues. Pannexin-1 oligomers have been shown to be functional single membrane channels that connect intracellular and extracellular compartments and are not intercellular channels in appositional membranes. The physiological functions of Pannexin-1 are to link to the adenosine triphosphate efflux that acts as a paracrine signal, and regulate cellular inflammasomes in a variety of cell types under physiological and pathophysiological conditions. However, there are still many functions to be explored. This review summarizes recent reports and discusses the role of Pannexin-1 in cardiovascular diseases, including ischemia, arrhythmia, cardiac fibrosis, and hypertension. Pannexin-1 has been suggested as an exciting, clinically relevant target in cardiovascular diseases.

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Role of Pannexin-1 hemichannels and purinergic receptors in the pathogenesis of human diseases

Cited by 75 publications

References 155 publications

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Extracellular chloride is required for efficient platelet aggregation

Pannexin-1 channels and their emerging functions in cardiovascular diseases

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