Pannexin 1, a large-pore membrane channel, contributes to hypotonicity-induced ATP release in Schwann cells

Wei, Zhongya; Qu, Hui-Lin; Dai, YuJuan; Wang, Qian; Ling, Zhuo-Min; Su, Wenfeng; Zhao, Yayu; Shen, Weisen; Chen, Gang

doi:10.4103/1673-5374.290911

Cited by 19 publications

(19 citation statements)

References 47 publications

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“…In contrast, ATP release by airway epithelial cells was detectable within seconds after a sudden osmotic stimulus, was reversible, and was attenuated by the Panx1 inhibitors CBX or probenecid ( Ransford et al, 2009 ). Similarly, ATP release by Schwann cells induced by hypotonicity was detectable within 2 min after the stimulus, occurred in the absence of the cytoplasmic marker lactate dehydrogenase, and was blocked by the same Panx1 inhibitors ( Wei et al, 2021 ). Furthermore, ATP release by oocytes expressing WT Panx1 or Panx1Δ378 was detectable in the unstirred supernatant as early as 5 min after a K + stimulus ( Wang and Dahl, 2018 ).…”

Section: Activation Of Panx1 By Caspase Cleavagementioning

confidence: 99%

Structure versus function: Are new conformations of pannexin 1 yet to be resolved?

Mim

Perkins

Dahl

2021

Journal of General Physiology

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Pannexin 1 (Panx1) plays a decisive role in multiple physiological and pathological settings, including oxygen delivery to tissues, mucociliary clearance in airways, sepsis, neuropathic pain, and epilepsy. It is widely accepted that Panx1 exerts its role in the context of purinergic signaling by providing a transmembrane pathway for ATP. However, under certain conditions, Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability. A recent flurry of publications has provided structural information about the Panx1 channel. However, while these structures are consistent with a chloride selective channel, none show a conformation with strong support for the ATP release function of Panx1. In this Viewpoint, we critically assess the existing evidence for the function and structure of the Panx1 channel and conclude that the structure corresponding to the ATP permeation pathway is yet to be determined. We also list a set of additional topics needing attention and propose ways to attain the large-pore, ATP-permeable conformation of the Panx1 channel.

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Section: Activation Of Panx1 By Caspase Cleavagementioning

confidence: 99%

Structure versus function: Are new conformations of pannexin 1 yet to be resolved?

Mim

Perkins

Dahl

2021

Journal of General Physiology

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“…Primary Schwann cell cultures were performed as previously described [ 18 ]. In brief, after isolation from the sciatic nerves, cells were incubated in DMEM containing 10% horse serum, and supplemented with 1 ng/ml heregulin β-1 (Peprotech, 100–03) and 0.5 μM forskolin (Sigma-Aldrich, F6886) for proliferation.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, Panx 1 activation in the dorsal root ganglion (DRG), astrocytes, and microglia participates in neuropathic pain development [ 15 – 17 ]. In addition, our previous study revealed that Panx 1 is highly expressed in Schwann cells compared with the other two family members and the inhibition of Panx 1 reduces hypotonicity-induced ATP release [ 18 ]. However, the contribution of Panx1 in Schwann cells regarding neuropathic pain is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses

Wang

Ling

et al. 2022

J Neuroinflammation

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Background Neuropathic pain is still a challenge for clinical treatment as a result of the comprehensive pathogenesis. Although emerging evidence demonstrates the pivotal role of glial cells in regulating neuropathic pain, the role of Schwann cells and their underlying mechanisms still need to be uncovered. Pannexin 1 (Panx 1), an important membrane channel for the release of ATP and inflammatory cytokines, as well as its activation in central glial cells, contributes to pain development. Here, we hypothesized that Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain. Methods A mouse model of chronic constriction injury (CCI) in CD1 adult mice or P0-Cre transgenic mice, and in vitro cultured Schwann cells were used. Intrasciatic injection with Panx 1 blockers or the desired virus was used to knock down the expression of Panx 1. Mechanical and thermal sensitivity was assessed using Von Frey and a hot plate assay. The expression of Panx 1 was measured using qPCR, western blotting, and immunofluorescence. The production of cytokines was monitored through qPCR and enzyme-linked immunosorbent assay (ELISA). Panx1 channel activity was detected by ethidium bromide (EB) uptake. Results CCI induced persistent neuroinflammatory responses and upregulation of Panx 1 in Schwann cells. Intrasciatic injection of Panx 1 blockers, carbenoxolone (CBX), probenecid, and Panx 1 mimetic peptide (10Panx) effectively reduced mechanical and heat hyperalgesia. Probenecid treatment of CCI-induced mice significantly reduced Panx 1 expression in Schwann cells, but not in dorsal root ganglion (DRG). In addition, Panx 1 knockdown in Schwann cells with Panx 1 shRNA-AAV in P0-Cre mice significantly reduced CCI-induced neuropathic pain. To determine whether Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain, we evaluated its effect in LPS-treated Schwann cells. We found that inhibition of Panx 1 via CBX and Panx 1-siRNA effectively attenuated the production of selective cytokines, as well as its mechanism of action being dependent on both Panx 1 channel activity and its expression. Conclusion In this study, we found that CCI-related neuroinflammation correlates with Panx 1 activation in Schwann cells, indicating that inhibition of Panx 1 channels in Schwann cells reduces neuropathic pain through the suppression of neuroinflammatory responses.

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“…Consistently, the inhibition of Rho kinase, Ras homolog family member A (RhoA) or myosin light chain (MLC) kinase, which disrupts the actin cytoskeleton, significantly reduces ATP release via mechanosensitive PANX1 channels [38]. Further, the treatment of Schwann cells using a Rho GTPase inhibitor or small interfering RNA (siRNA) targeting Rho or cytochalasin D results in a decrease in hypotonicity-induced ATP release via PANX1 [61]. In addition, PANX1 is associated with collapsing response mediator protein 2 (Crmp2), which is a well-known microtubule-stabilizing protein [62].…”

Section: Force-from-filaments Modelmentioning

confidence: 95%

Mechanisms of Pannexin 1 (PANX1) Channel Mechanosensitivity and Its Pathological Roles

Yang

Xiao

et al. 2022

IJMS

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Pannexins (PANX) were cloned based on their sequence homology to innexins (Inx), invertebrate gap junction proteins. Although there is no sequence homology between PANX and connexins (Cx), these proteins exhibit similar configurations. The PANX family has three members, PANX1, PANX2 and PANX3. Among them, PANX1 has been the most extensively studied. The PANX1 channels are activated by many factors, including high extracellular K+ ([K+]e), high intracellular Ca2+ ([Ca2+]i), Src family kinase (SFK)-mediated phosphorylation, caspase cleavage and mechanical stimuli. However, the mechanisms mediating this mechanosensitivity of PANX1 remain unknown. Both force-from-lipids and force-from-filaments models are proposed to explain the gating mechanisms of PANX1 channel mechanosensitivity. Finally, both the physiological and pathological roles of mechanosensitive PANX1 are discussed.

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Pannexin 1, a large-pore membrane channel, contributes to hypotonicity-induced ATP release in Schwann cells

Cited by 19 publications

References 47 publications

Structure versus function: Are new conformations of pannexin 1 yet to be resolved?

Structure versus function: Are new conformations of pannexin 1 yet to be resolved?

Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses

Mechanisms of Pannexin 1 (PANX1) Channel Mechanosensitivity and Its Pathological Roles

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