Pannexin 1 as a driver of inflammation and ischemia–reperfusion injury

Koval, Michael; Cwiek, Aleksandra; Carr, Thomas H.; Good, Miranda E.; Lohman, Alexander W.; Isakson, Brant E.

doi:10.1007/s11302-021-09804-8

Cited by 26 publications

(21 citation statements)

References 109 publications

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“…Panx1 channels are indispensable in inflammation [ 5 , 6 , 12 , 15 , 17 , 44 ]. Their channel opening is triggered by a number of stimuli, including high extracellular potassium levels.…”

Section: Resultsmentioning

confidence: 99%

“…Inflammation is regulated by a myriad of entangled communication networks. In recent years, cellular channels composed of pannexin proteins have emerged as key players in the onset and exacerbation of inflammation [ 5 , 6 ]. Pannexins are transmembrane proteins that form channels connecting the cytosol to the extracellular environment.…”

Section: Introductionmentioning

confidence: 99%

“…When opened, Panx1 channels form transmembrane conduits, allowing the passage of ions and molecules of less than 1 kilodalton (kDa), including adenosine triphosphate (ATP) [ 9 , 10 , 11 ]. Panx1 channels have been broadly linked to cell death [ 9 , 11 ] and inflammatory processes [ 5 , 6 , 12 , 13 , 14 ]. More specifically, Panx1 channels contribute to inflammatory responses by facilitating cleavage of pro-caspase1 in the NACHT-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome, a multiprotein complex that activates interleukin 1β and interleukin 18 [ 12 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

Caufriez

Tabernilla

Campenhout

et al. 2022

IJMS

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Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.

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“…Panx1 channels are indispensable in inflammation [ 5 , 6 , 12 , 15 , 17 , 44 ]. Their channel opening is triggered by a number of stimuli, including high extracellular potassium levels.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

Caufriez

Tabernilla

Campenhout

et al. 2022

IJMS

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show abstract

“…Thus, Panx1 participates in a plethora of physiological processes. In addition, these channels regulate the course of pathophysiological processes including inflammation and cell death ( Dahl and Keane, 2012 ; Koval et al, 2021 ).…”

Section: Panx1 Channel Properties and Physiological Functionmentioning

confidence: 99%

Pannexin1 channels—a potential therapeutic target in inflammation

Rusiecka

Tournier

Molica

et al. 2022

Front. Cell Dev. Biol.

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An exaggerated inflammatory response is the hallmark of a plethora of disorders. ATP is a central signaling molecule that orchestrates the initiation and resolution of the inflammatory response by enhancing activation of the inflammasome, leukocyte recruitment and activation of T cells. ATP can be released from cells through pannexin (Panx) channels, a family of glycoproteins consisting of three members, Panx1, Panx2, and Panx3. Panx1 is ubiquitously expressed and forms heptameric channels in the plasma membrane mediating paracrine and autocrine signaling. Besides their involvement in the inflammatory response, Panx1 channels have been shown to contribute to different modes of cell death (i.e., pyroptosis, necrosis and apoptosis). Both genetic ablation and pharmacological inhibition of Panx1 channels decrease inflammation in vivo and contribute to a better outcome in several animal models of inflammatory disease involving various organs, including the brain, lung, kidney and heart. Up to date, several molecules have been identified to inhibit Panx1 channels, for instance probenecid (Pbn), mefloquine (Mfq), flufenamic acid (FFA), carbenoxolone (Cbx) or mimetic peptides like 10Panx1. Unfortunately, the vast majority of these compounds lack specificity and/or serum stability, which limits their application. The recent availability of detailed structural information on the Panx1 channel from cryo-electron microscopy studies may open up innovative approaches to acquire new classes of synthetic Panx1 channel blockers with high target specificity. Selective inhibition of Panx1 channels may not only limit acute inflammatory responses but may also prove useful in chronic inflammatory diseases, thereby improving human health. Here, we reviewed the current knowledge on the role of Panx1 in the initiation and resolution of the inflammatory response, we summarized the effects of Panx1 inhibition in inflammatory pathologies and recapitulate current Panx1 channel pharmacology with an outlook towards future approaches.

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“…Pannexin1 channels are heptameric conduits that allow the passage of ions and other molecules such as adenosine triphosphate (ATP) across the cell plasma membrane, thereby playing a role in multiple pathophysiological responses linked to inflammation [1,2]. Although pannexin1 channels are seen as highly interesting drug targets, the search for appropriate blockers is an arduous process [3,4].…”

Section: Introductionmentioning

confidence: 99%