Stimulation of the A2B Adenosine Receptor Subtype Enhances Connexin26 Hemichannel Activity in Small Airway Epithelial Cells

Dierks, Anne; Bader, Almke; Lehrich, Tina; Ngezahayo, Anaclet

doi:10.33594/000000160

Cited by 7 publications

(22 citation statements)

References 65 publications

(99 reference statements)

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“…As a GJ inhibitor, CBX has significant effects in pain reduction ( 23 ), ameliorating Px1 channel activity by regulating the first extracellular loop ( 16 ). In addition, CBX has been found to have potential effects on potentially suppressing neuropathic antitumor drug-induced pain by blocking astrocyte GJs and inhibiting the increase of GFAP levels in the spinal cord ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, non-neuronal cells also initiate pain through the release of cytokines triggered by extracellular ATP binding to its receptor ( 15 ). However, another study revealed that a reduction in the expression of one GJ protein could cause an increase in that of another ( 16 ). Therefore, the present study aimed to determine whether Px1 and Cx43 are involved in the formation of acute pain, and whether this can be relieved by the intrathecal injection of CBX.…”

Section: Introductionmentioning

confidence: 99%

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Carbenoxolone has the potential to ameliorate acute incision pain in rats

2021

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Carbenoxolone (CBX) is primarily used to relieve various types of neuropathic and inflammatory pain. However, little is known concerning the role of CBX in acute pain and its functional mechanisms therein and this was investigated in the present study. Rats underwent toe incision and behavioral tests were performed to assess mechanical hypersensitivity. The expression levels of pannexin 1 (Px1) and connexin 43 (Cx43) were detected using western blot analysis 2, 4, 6 or 24 h after toe incision, and the expression of TNF-α, IL-1β and P substance (SP) was determined by ELISA; Px1 and Cx43 expression was also examined by immunofluorescence staining. At 2, 6 and 12 h post-toe incision, the postoperative pain threshold was significantly reduced, which was subsequently recovered at 2 and 6 h post-surgery following pretreatment with CBX or pannexin 1 mimetic inhibitory peptide. CBX reduced Px1 levels at 4 and 24 h post-incision. However, Cx43 levels were reduced by CBX as little as 2 h post-surgery. Furthermore, CBX not only distinctly decreased the levels of Px1 and Cx43, but also reduced the co-localization of Px1 or Cx43 with glial fibrillary acidic protein, 2 h after incision. It was also observed that the protein levels of inflammatory makers (IL-1β, SP and TNF-α) showed a tendency to decline at 2, 4, 6 and 24 h after incision. Collectively, the expression of Px1 and Cx43 in astrocytes may be involved in pain behaviors diminished by CBX, and CBX potentially reduces acute pain by decreasing Px1 and Cx43 levels. Px1 and Cx43 from spinal astrocytes may serve important roles in the early stages and maintenance of acute pain, while preoperative injection of CBX has the potential to relieve hyperalgesia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Carbenoxolone has the potential to ameliorate acute incision pain in rats

2021

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“…In order to analyse the functionality of the formed Cx hemichannels in the membrane of transfected cells, we performed dye uptake experiments [11], [34], [35], [36]. The functionality of Cx hemichannels was recognized as an accelerated increase of fluorescence intensity of the dye ethidium bromide (Etd) in the cells in response to the removal of external Ca 2+ as compared to control conditions with 2 mM external Ca 2+ (Figure 2a).…”

Section: Functionality Of Expressed CX Hemichannelsmentioning

confidence: 99%

“…The mechanisms that lead to the increased activity of Cx hemichannels under the mentioned pathological conditions are still matter of ongoing research. Due to experimental convenience, an increased expression of mainly Cx43 has been extensively reported [11], [12], [13]. Likewise, the link between the activity of Cx hemichannels and the pathological status is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

The Bioactive Phenolic Agents Diaryl Ether CVB2-61 and Diarylheptanoid CVB4-57 as Connexin Hemichannel Blocker

Dierks¹,

Vanucci-Bacqué²,

Schäfer³

et al. 2022

Preprint

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Inflammation mediators enhance the activity of connexin (Cx) hemichannels especially in the epithelial and endothelial tissues. As potential release route for injury signals like (oligo)nucleotides, Cx hemichannels may contribute to long lasting inflammation. Specific inhibition of Cx hemichannels may therefore be a mode of prevention and treatment of long lasting, chronic sterile inflammation. The activity of Cx hemichannels was analysed in N2A and HeLa cells transfected with human Cx26 and Cx46 as well as in Calu-3 cells using the dye uptake as functional assay. Moreover, possible impact of the bioactive phenolic agents CVB2-61 and CVB4-57 on the barrier function of epithelial cells was analysed using Calu-3 cells. Both agents inhibited the dye uptake in N2A cells expressing Cx26 (> 5 µM) and Cx46 (> 20 µM). In Calu-3 cells, CVB2-61 and CVB4-57 reversible inhibited the dye uptake at concentrations as low as 5 µM, without affecting the gap junction communication and barrier function, even at concentrations of 20 µM. While CVB2-61 or CVB4-57 maintained a reduced dye uptake in Calu-3 cells, an enhancement of the dye uptake in response to stimulation of adenosine signaling was still observed after removal of the agents. The report shows that CVB2-61 and CVB4-57 reversible block Cx hemichannels. Deciphering the interaction mechanisms with Cx hemichannels could allow further development of phenolic compounds to target Cx hemichannels for a better and safer use in treatment of pathologies that involve Cx hemichannels.

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“…In mice, the sustained expression of CX26-induced epidermal hyperproliferation blocked the transition to tissue remodelling and caused the infiltration of the inflammatory cells, finally leading to the development of psoriasis-like inflammation [101]. Mechanistically, the ectopic expression of CX26 in keratinocytes resulted in increased ATP [102]. The expression of this connexin undergoes a huge increase in psoriatic patients.…”

Section: Figurementioning

confidence: 99%

Purinergic Signaling and Inflammasome Activation in Psoriasis Pathogenesis

Ferrari

Casciano

Secchiero

et al. 2021

IJMS

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Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques’ formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes’ inflammasome may trigger early inflammatory pathways involving IL-1β production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments.

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Stimulation of the A2B Adenosine Receptor Subtype Enhances Connexin26 Hemichannel Activity in Small Airway Epithelial Cells

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 7 publications

References 65 publications

Carbenoxolone has the potential to ameliorate acute incision pain in rats

Carbenoxolone has the potential to ameliorate acute incision pain in rats

The Bioactive Phenolic Agents Diaryl Ether CVB2-61 and Diarylheptanoid CVB4-57 as Connexin Hemichannel Blocker

Purinergic Signaling and Inflammasome Activation in Psoriasis Pathogenesis

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