Nitric oxide inhibits the pannexin 1 channel through a cGMP–PKG dependent pathway

Background & AimsThe concept of enteric glia as regulators of intestinal homeostasis is slowly gaining acceptance as a central concept in neurogastroenterology. Yet how glia contribute to intestinal disease is still poorly understood. Purines generated during inflammation drive enteric neuron death by activating neuronal P2X7 purine receptors (P2X7R); triggering adenosine triphosphate (ATP) release via neuronal pannexin-1 channels that subsequently recruits intracellular calcium ([Ca2+]i) in surrounding enteric glia. We tested the hypothesis that the activation of enteric glia contributes to neuron death during inflammation.MethodsWe studied neuroinflammation in vivo using the 2,4-dinitrobenzene sulfonic acid model of colitis and in situ using whole-mount preparations of human and mouse intestine. Transgenic mice with a targeted deletion of glial connexin-43 (Cx43) [GFAP::CreERT2+/−/Cx43f/f] were used to specifically disrupt glial signaling pathways. Mice deficient in inducible nitric oxide (NO) synthase (iNOS−/−) were used to study NO production. Protein expression and oxidative stress were measured using immunohistochemistry and in situ Ca2+ and NO imaging were used to monitor glial [Ca2+]i and [NO]i.ResultsPurinergic activation of enteric glia drove [Ca2+]i responses and enteric neuron death through a Cx43-dependent mechanism. Neurotoxic Cx43 activity, driven by NO production from glial iNOS, was required for neuron death. Glial Cx43 opening liberated ATP and Cx43-dependent ATP release was potentiated by NO.ConclusionsOur results show that the activation of glial cells in the context of neuroinflammation kills enteric neurons. Mediators of inflammation that include ATP and NO activate neurotoxic pathways that converge on glial Cx43 hemichannels. The glial response to inflammatory mediators might contribute to the development of motility disorders.

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“…This result is in agreement with other studies showing that NO inhibits panx1 channel activity. 35 , 36 …”

Section: Resultsmentioning

confidence: 99%

Enteric Glia Mediate Neuron Death in Colitis Through Purinergic Pathways That Require Connexin-43 and Nitric Oxide

Brown

McClain

Watson

et al. 2016

Cellular and Molecular Gastroenterology and Hepatology

144

188

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“…An inhibitory effect of NO in a cGMP/PKG dependent way was demonstrated by Poornima et al . [ 143 ]. They showed that NO donors reduced Panx1 currents in HEK293 cells and that inhibition of the soluble guanylate cyclase or of PKG blocked the NO effect [ 143 ].…”

Section: Regulation Of Gjs and Hcs By The Redox Potentialmentioning

confidence: 99%

Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: a revision

et al. 2016

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Post-translational modifications of connexins play an important role in the regulation of gap junction and hemichannel permeability. The prerequisite for the formation of functional gap junction channels is the assembly of connexin proteins into hemichannels and their insertion into the membrane. Hemichannels can affect cellular processes by enabling the passage of signaling molecules between the intracellular and extracellular space. For the intercellular communication hemichannels from one cell have to dock to its counterparts on the opposing membrane of an adjacent cell to allow the transmission of signals via gap junctions from one cell to the other. The controlled opening of hemichannels and gating properties of complete gap junctions can be regulated via post-translational modifications of connexins. Not only channel gating, but also connexin trafficking and assembly into hemichannels can be affected by post-translational changes. Recent investigations have shown that connexins can be modified by phosphorylation/dephosphorylation, redox-related changes including effects of nitric oxide (NO), hydrogen sulfide (H2S) or carbon monoxide (CO), acetylation, methylation or ubiquitination. Most of the connexin isoforms are known to be phosphorylated, e.g. Cx43, one of the most studied connexin at all, has 21 reported phosphorylation sites. In this review, we provide an overview about the current knowledge and relevant research of responsible kinases, connexin phosphorylation sites and reported effects on gap junction and hemichannel regulation. Regarding the effects of oxidants we discuss the role of NO in different cell types and tissues and recent studies about modifications of connexins by CO and H2S.

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“…Overexpression of Panx1 in cancer [211], its inhibition reduces tumour growth and invasiveness [212]. NO may inhibit Panx1 current [213] Extracellular vesicles (EVs)…”

Section: Unknownmentioning

confidence: 99%

Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments

Privat-Maldonado

Bengtson

Razzokov

et al. 2019

Cancers

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Tumours are complex systems formed by cellular (malignant, immune, and endothelial cells, fibroblasts) and acellular components (extracellular matrix (ECM) constituents and secreted factors). A close interplay between these factors, collectively called the tumour microenvironment, is required to respond appropriately to external cues and to determine the treatment outcome. Cold plasma (here referred as ‘plasma’) is an emerging anticancer technology that generates a unique cocktail of reactive oxygen and nitrogen species to eliminate cancerous cells via multiple mechanisms of action. While plasma is currently regarded as a local therapy, it can also modulate the mechanisms of cell-to-cell and cell-to-ECM communication, which could facilitate the propagation of its effect in tissue and distant sites. However, it is still largely unknown how the physical interactions occurring between cells and/or the ECM in the tumour microenvironment affect the plasma therapy outcome. In this review, we discuss the effect of plasma on cell-to-cell and cell-to-ECM communication in the context of the tumour microenvironment and suggest new avenues of research to advance our knowledge in the field. Furthermore, we revise the relevant state-of-the-art in three-dimensional in vitro models that could be used to analyse cell-to-cell and cell-to-ECM communication and further strengthen our understanding of the effect of plasma in solid tumours.

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Nitric oxide inhibits the pannexin 1 channel through a cGMP–PKG dependent pathway

Cited by 40 publications

References 25 publications

Enteric Glia Mediate Neuron Death in Colitis Through Purinergic Pathways That Require Connexin-43 and Nitric Oxide

Enteric Glia Mediate Neuron Death in Colitis Through Purinergic Pathways That Require Connexin-43 and Nitric Oxide

Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: a revision

Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments

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