Pannexin-1 Activation by Phosphorylation Is Crucial for Platelet Aggregation and Thrombus Formation

Metz, Lisa Maria; Elvers, Margitta

doi:10.3390/ijms23095059

Cited by 13 publications

(21 citation statements)

References 31 publications

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“…This in turn amplifies P2×1 receptor activation and thus calcium flux important for platelet activation and aggregation. The activation of Panx1 channels by Src kinases is crucial for the phosphorylation of Panx1 at Tyr 198 and Tyr 308 , suggesting that Src kinases are key regulators in Panx1 activation in platelets (13, 18). Beside GPVI mediated activation of Panx1, G protein-coupled receptor activation and thromboxane mediated signaling pathways are able to amplify Panx1 phosphorylation (13).…”

Section: Discussionmentioning

confidence: 99%

“…The activation of Panx1 channels by Src kinases is crucial for the phosphorylation of Panx1 at Tyr 198 and Tyr 308 , suggesting that Src kinases are key regulators in Panx1 activation in platelets (13, 18). Beside GPVI mediated activation of Panx1, G protein-coupled receptor activation and thromboxane mediated signaling pathways are able to amplify Panx1 phosphorylation (13). Panx1 activation and subsequent non-vesicular ATP release from platelets amplifies thrombus formation and therefore plays an important role in hemostasis and thrombosis (13, 18).…”

Section: Discussionmentioning

confidence: 99%

“…Beside GPVI mediated activation of Panx1, G protein-coupled receptor activation and thromboxane mediated signaling pathways are able to amplify Panx1 phosphorylation (13). Panx1 activation and subsequent non-vesicular ATP release from platelets amplifies thrombus formation and therefore plays an important role in hemostasis and thrombosis (13,18). Due to the important role of extracellular ATP as inflammatory molecule (21,22), a role for Panx1 in inflammation was discovered by different groups.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In platelets, Panx1 channels are exposed at the plasma membrane to release ATP upon platelet stimulation with thrombin, collagen or the TxA 2 analogue U46619 (13, 14). Platelet activation leads to increased Panx1 phosphorylation at Tyr 198 and Tyr 308 via the Src-GPVI signaling axes to support arterial thrombus formation (13). Clinical and experimental data suggest that platelets play a pivotal role in AAA pathology because impaired endothelial function causes platelet activation and promotes a persistent renewal of cellular activity at the luminal interface of the ILT via entrapment and recruitment of activated platelets to establish a chronic inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

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Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

Metz

Feige

Biasi

et al. 2022

Preprint

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Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in AAA formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP)VI. Since platelets play a role in cardiovascular diseases including AAA, we analyzed the contribution of platelet Panx1 in the progression of AAA. We detected enhanced Panx1 plasma levels in AAA patients. In experimental AAA using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect AAA formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in AAA via Panx1 channels and adds important knowledge about the significance of platelets in AAA pathology important for the establishment of an anti-platelet therapy for AAA patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

Metz

Feige

Biasi

et al. 2022

Preprint

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Platelet transcriptome analysis in patients with germline RUNX1 mutations

Palma-Barqueros

Bastida

Andreo

et al. 2023

Journal of Thrombosis and Haemostasis

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TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer

Huang,

Chiang,

Lin

et al. 2024

Cell Death Dis

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ATP and its receptor P2RX7 exert a pivotal effect on antitumor immunity during chemotherapy-induced immunogenic cell death (ICD). Here, we demonstrated that TNFα-mediated PANX1 cleavage was essential for ATP release in response to chemotherapy in colorectal cancer (CRC). TNFα promoted PANX1 cleavage via a caspase 8/3-dependent pathway to enhance cancer cell immunogenicity, leading to dendritic cell maturation and T-cell activation. Blockade of the ATP receptor P2RX7 by the systemic administration of small molecules significantly attenuated the therapeutic efficacy of chemotherapy and decreased the infiltration of immune cells. In contrast, administration of an ATP mimic markedly increased the therapeutic efficacy of chemotherapy and enhanced the infiltration of immune cells in vivo. High PANX1 expression was positively correlated with the recruitment of DCs and T cells within the tumor microenvironment and was associated with favorable survival outcomes in CRC patients who received adjuvant chemotherapy. Furthermore, a loss-of-function P2RX7 mutation was associated with reduced infiltration of CD8+ immune cells and poor survival outcomes in patients. Taken together, these results reveal that TNFα-mediated PANX1 cleavage promotes ATP-P2RX7 signaling and is a key determinant of chemotherapy-induced antitumor immunity.

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Pannexin-1 Activation by Phosphorylation Is Crucial for Platelet Aggregation and Thrombus Formation

Cited by 13 publications

References 31 publications

Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

Platelet transcriptome analysis in patients with germline RUNX1 mutations

TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer

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