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

Yang, Kai; Xiao, Zhupeng; He, Xueai; Weng, Ruotong; Zhao, Xinyue; Sun, Taolei

doi:10.3390/ijms23031523

Cited by 17 publications

(12 citation statements)

References 78 publications

(122 reference statements)

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“…This rapid Ca 2þ amplification mechanism is shared by many cell types, including endothelial cells [11], cholangiocytes (epithelial cells) [12], and erythrocytes [13]. More likely than not it explains Panx1's apparent mechanosensitivity [14]. Of note, Panx1 also amplifies and relays GPVI signals to P2X1 in platelets [15].…”

Section: Mechanosensing Of Membrane Stretchingmentioning

confidence: 99%

Platelet mechanosensing as key to understanding platelet function

Schoen,

Kenny,

Patil

2023

Current Opinion in Hematology

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Purpose of review This review highlights how the perception of platelet function is evolving based on recent insights into platelet mechanobiology. Recent findings The mechanosensitive ion channel Piezo1 mediates activation of free-flowing platelets under conditions of flow acceleration through mechanisms independent of adhesion receptors and classical activation pathways. Interference with the initiation of platelet migration or with the phenotypic switch of migrating platelets to a procoagulant state aggravates inflammatory bleeding. Mechanosensing of biochemical and biophysical microenvironmental cues during thrombus formation feed into platelet contractile force generation. Measurements of single platelet contraction and bulk clot retraction show promise to identify individuals at risk for hemorrhage. Summary New findings unravel novel mechanotransduction pathways and effector functions in platelets, establishing mechanobiology as a pivotal component of platelet function. These insights highlight limitations of existing treatments and offer new potential therapeutic approaches and diagnostic avenues based on mechanobiological principles. Further extensive research is required to distinguish between core hemostatic and pathological mechanisms influenced by platelet mechanosensing.

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Section: Mechanosensing Of Membrane Stretchingmentioning

confidence: 99%

Platelet mechanosensing as key to understanding platelet function

Schoen,

Kenny,

Patil

2023

Current Opinion in Hematology

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“…9,51 The elevated extracellular K + level contributes to ATP release by activating the pannexin-1 (Panx1) hemichannels. 52,53 It creates a vicious cycle that results in the continuous efflux of K + ions. 54 Several studies have suggested an association between reduced intracellular K + levels and NLRP3 activation, but the mechanistic link remains poorly understood.…”

Section: Activation Of the Nlrp3 Inflammasomementioning

confidence: 99%

“…Also, the dead or dying cells in the ischemic area passively release ATP. This extracellular ATP activates the purinergic receptors (P2X4 and P2X7) on nearby cells, resulting in K + ion efflux. , The elevated extracellular K + level contributes to ATP release by activating the pannexin-1 (Panx1) hemichannels. , It creates a vicious cycle that results in the continuous efflux of K + ions . Several studies have suggested an association between reduced intracellular K + levels and NLRP3 activation, but the mechanistic link remains poorly understood.…”

Section: Low Intracellular Potassium (K+) Ions or K+ Effluxmentioning

confidence: 99%

Role of NLRP3 Inflammasome in Stroke Pathobiology: Current Therapeutic Avenues and Future Perspective

Panbhare,

Pandey,

Chauhan

et al. 2023

ACS Chem. Neurosci.

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Neuroinflammation is a key pathophysiological feature of stroke-associated brain injury. A local innate immune response triggers neuroinflammation following a stroke via activating inflammasomes. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has been heavily implicated in stroke pathobiology. Following a stroke, several stimuli have been suggested to trigger the assembly of the NLRP3 inflammasome. Recent studies have advanced the understanding and revealed several new players regulating NLRP3 inflammasome-mediated neuroinflammation. This article discussed recent advancements in NLRP3 assembly and highlighted stroke-induced mitochondrial dysfunction as a major checkpoint to regulating NLRP3 activation. The NLRP3 inflammasome activation leads to caspase-1-dependent maturation and release of IL-1β, IL-18, and gasdermin D. In addition, genetic or pharmacological inhibition of the NLRP3 inflammasome activation and downstream signaling has been shown to attenuate brain infarction and improve the neurological outcome in experimental models of stroke. Several drug-like small molecules targeting the NLRP3 inflammasome are in different phases of development as novel therapeutics for various inflammatory conditions, including stroke. Understanding how these molecules interfere with NLRP3 inflammasome assembly is paramount for their better optimization and/or development of newer NLRP3 inhibitors. In this review, we summarized the assembly of the NLRP3 inflammasome and discussed the recent advances in understanding the upstream regulators of NLRP3 inflammasomemediated neuroinflammation following stroke. Additionally, we critically examined the role of the NLRP3 inflammasome-mediated signaling in stroke pathophysiology and the development of therapeutic modalities to target the NLRP3 inflammasome-related signaling for stroke treatment.

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“…It is well known that Panx‐1 operates as a damage‐associated molecular pattern (DAMP) molecule in the regulation of ATP release. As a result, extracellular ATP concentration increase due to cellular damage or stress through the Panx‐1 ion channel (Yang et al., 2022). Subsequently, extracellular ATP activates the P2X7 receptor, resulting in the NLRP3 activation and triggering an inflammatory response (Pelegrin, 2021).…”

Section: Introductionmentioning

confidence: 99%

Baicalin inhibits monosodium urate crystal‐induced pyroptosis in renal tubular epithelial cell line through Panx‐1/P2X7 pathways: Molecular docking, molecular dynamics, and in vitro experiments

Fu,

Liu,

Wang

et al. 2024

Chem Biol Drug Des

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Pyroptosis is a programmed cell death process that frequently occurs in many diseases, including hyperuricemic nephropathy (HN). In HN, a range of stimuli mediates inflammation, leading to the activation of inflammasomes and the production of gasdermin D (GSDMD). Baicalin (BA), a natural flavonoid renowned for its antioxidant and anti‐inflammatory properties, was investigated for its role in HN in this study. Initially, HN‐like inflammation and pyroptosis were induced in HK‐2 cells with treatment of monosodium urate (MSU), followed by the BA treatment. The expression of pyroptosis‐associated genes, Panx‐1 and P2X7, at both mRNA and protein levels was assessed through real‐time polymerase chain reaction (RT‐qPCR) and Western blotting (WB) without or with BA treatment. The results showed that expression of Panx‐1 and P2X7 at mRNA and protein levels was increased in MSU‐treated HK‐2 cells, which subsequently decreased upon the BA treatment. Further experiments showed that BA could combine NLRP3 inflammasome and GSDMD, destabilizing GSDMD protein. Moreover, BA protected the cell membrane from MSU‐induced damage, as evidenced by Hoechst 33342 and PI double staining, lactate dehydrogenase (LDH) assays, and electron microscopy observations. These results suggest that BA is involved in the regulating Panx‐1/P2X7 pathways and thus inhibits pyroptosis, highlighting its potential therapeutic effect for HN.

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

Cited by 17 publications

References 78 publications

Platelet mechanosensing as key to understanding platelet function

Platelet mechanosensing as key to understanding platelet function

Role of NLRP3 Inflammasome in Stroke Pathobiology: Current Therapeutic Avenues and Future Perspective

Baicalin inhibits monosodium urate crystal‐induced pyroptosis in renal tubular epithelial cell line through Panx‐1/P2X7 pathways: Molecular docking, molecular dynamics, and in vitro experiments

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