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Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation.

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TLDR
It is reported that the ATP-release channel Pannexin1 (Panx1) opens downstream of EC activation by TNF-α, placing Panx1 channels at the centre of cytokine crosstalk with purinergic signalling in the endothelium.
Abstract
Inflammatory cell recruitment to local sites of tissue injury and/or infection is controlled by a plethora of signalling processes influencing cell-to-cell interactions between the vascular endothelial cells (ECs) in post-capillary venules and circulating leukocytes. Recently, ATP-sensitive P2Y purinergic receptors have emerged as downstream regulators of EC activation in vascular inflammation. However, the mechanism(s) regulating cellular ATP release in this response remains elusive. Here we report that the ATP-release channel Pannexin1 (Panx1) opens downstream of EC activation by TNF-α. This process involves activation of type-1 TNF receptors, recruitment of Src family kinases (SFK) and SFK-dependent phosphorylation of Panx1. Using an inducible, EC-specific Panx1 knockout mouse line, we report a previously unidentified role for Panx1 channels in promoting leukocyte adhesion and emigration through the venous wall during acute systemic inflammation, placing Panx1 channels at the centre of cytokine crosstalk with purinergic signalling in the endothelium.

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The Cryo-EM Structure of a Pannexin 1 Channel Reveals an Extracellular Gating Mechanism

TL;DR: The structural and functional study establishes the extracellular loops as the unique structural determinants for channel gating and inhibition in Panx1 thereby providing the founding model to study pannexins.
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Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function

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References
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Book ChapterDOI

Receptors for Purines and Pyrimidines

TL;DR: In this review particular emphasis is placed on the discrepancy between the concentrations ofadenosine, ADP, and ATP in the purine receptors of UDP and UTP.
Journal ArticleDOI

Getting to the site of inflammation: the leukocyte adhesion cascade updated

TL;DR: This Review focuses on new aspects of one of the central paradigms of inflammation and immunity — the leukocyte adhesion cascade.
Journal ArticleDOI

Nitric oxide: an endogenous modulator of leukocyte adhesion.

TL;DR: Data suggest that endothelium-derived NO may be an important endogenous modulator of leukocyte adherence and that impairment of NO production results in a pattern ofLeukocyte adhesion and emigration that is characteristic of acute inflammation.
Journal ArticleDOI

Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor

TL;DR: Pannexin‐1, a recently described mammalian protein that functions as a hemichannel when ectopically expressed, is identified as this dye‐uptake pathway and signalling through pannexin•1 is required for processing of caspase‐1 and release of mature IL‐1β induced by P2X7 receptor activation.
Journal ArticleDOI

Intravascular danger signals guide neutrophils to sites of sterile inflammation.

TL;DR: Dynamic in vivo imaging revealed a multistep hierarchy of directional cues that guide neutrophil localization to sites of sterile inflammation, and the underlying mechanisms of recruitment of neutrophils into injured tissue.
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