Purinergic P2Y2 receptors modulate endothelial sprouting

Mühleder, Severin; Fuchs, Christiane; Basílio, José; Szwarc, Dorota; Pill, Karoline; Labuda, Krystyna; Slezak, Paul; Siehs, Christian; Pröll, Johannes; Priglinger, Eleni; Hoffmann, Carsten; Junger, Wolfgang G.; Redl, Heinz; Holnthoner, Wolfgang

doi:10.1007/s00018-019-03213-2

Cited by 20 publications

(20 citation statements)

References 51 publications

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“…18 The pBMN-P2Y11-YFP (yellow fluorescent protein) plasmid was a kind gift from Severin Mühleder and Wolfgang Holnthoner (Ludwig Boltzmann Institute for Clinical and Experimental Traumatology, Vienna, Austria). 29 The CMV-mito-CAR-Geco plasmid was obtained from Addgene (#46022; Addgene, Cambridge, MA, USA). 30 A mixture of four siRNAs targeting the P2Y11 receptor (SMARTpool siRNA) was purchased from Dharmacon (Lafayette, CO, USA).…”

Section: Transfection and Retroviral Infectionmentioning

confidence: 99%

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

Ledderose

Bromberger

Slubowski

et al. 2020

Journal of Leukocyte Biology

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T cells form an immune synapse (IS) with antigen-presenting cells (APCs) to detect antigens that match their TCR. Mitochondria, pannexin-1 (panx1) channels, and P2X4 receptors congregate at the IS where mitochondria produce the ATP that panx1 channels release in order to stimulate P2X4 receptors. P2X4 receptor stimulation causes cellular Ca 2+ influx that up-regulates mitochondrial metabolism and localized ATP production at the IS. Here we show that P2Y11 receptors are essential players that sustain these T cell activation mechanisms. We found that P2Y11 receptors retract from the IS toward the back of cells where their stimulation by extracellular ATP induces cAMP/PKA signaling that redirects mitochondrial trafficking to the IS. P2Y11 receptors thus reinforce IS signaling by promoting the aggregation of mitochondria with panx1 ATP release channels and P2X4 receptors at the IS. This dual purinergic signaling mechanism involving P2X4 and P2Y11 receptors focuses mitochondrial metabolism to the IS where localized ATP production sustains synaptic activity in order to allow successful completion of T cell activation responses. Our findings have practical implications because rodents lack P2Y11 receptors, raising concerns as to the validity of rodent models to study treatment of infections and inflammatory conditions.

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Section: Transfection and Retroviral Infectionmentioning

confidence: 99%

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

Ledderose

Bromberger

Slubowski

et al. 2020

Journal of Leukocyte Biology

Self Cite

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“…Like other GPCRs, P2Y 2 receptor can transactivate growth factor receptors, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor-2 (VEGFR-2) [ 43 ]. In recombinant 1321N1 astrocytoma cells, P2Y 2 agonist induces direct interaction of Src with the SH3 binding sites in the P2Y 2 receptor to facilitate Src activation, which then recruits the EGFR into a protein complex with the P2Y 2 receptor and allows Src to phosphorylate and activate the EGFR [ 44 ].…”

Section: P2y 2 Receptormentioning

confidence: 99%

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Klaver

Thurnher

2021

Cells

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Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.

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“…While, to our knowledge, no documented effects of connexin hemichannel function on tumor angiogenesis have been reported, it is tempting to speculate that many molecules found in the tumor microenvironment that would be permeable to hemichannels may affect vessel formation. Nucleotides including ATP and UTP released from breast cancer cells stimulated P2Y purinoceptor 2 (P2Y2R) [151], which can induce vascular sprouting [152]. Ca 2+ [153,154] and the cAMP-dependent kinase PKA [155] have also been shown to affect angiogenesis.…”

Section: Connexin Hemichannelsmentioning

confidence: 99%

Connexins in Cancer: Jekyll or Hyde?

2020

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The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and perform non-junctional intracellular activities. Historically, connexins have been considered tumor suppressors; however, they can also serve tumor-promoting functions in some contexts. Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function upstream of most, if not all, of the hallmarks of cancer. The development of advanced connexin targeting approaches remains an opportunity for the field to further interrogate the role of connexins in cancer phenotypes, particularly through the use of in vivo models. More specific modulators of connexin function will both help elucidate the functions of connexins in cancer and advance connexin-specific therapies in the clinic.

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Purinergic P2Y2 receptors modulate endothelial sprouting

Cited by 20 publications

References 51 publications

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Connexins in Cancer: Jekyll or Hyde?

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