Inhibitors of the 5-lipoxygenase pathway activate pannexin1 channels in macrophages via the thromboxane receptor
Autor: | Naman K. Patel, Maria Nathalia de Lira, David C. Spray, Pedro M. Persechini, Eliana Scemes, Hercules A. da Silva-Souza |
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Rok vydání: | 2014 |
Předmět: |
Male
Cell signaling Eicosanoid receptor Physiology Thromboxane Receptors Thromboxane Nerve Tissue Proteins Biology Connexins Cell Line Membrane Potentials Thromboxane receptor Mice Adenosine Triphosphate Cyclic AMP medicine Animals Lipoxygenase Inhibitors Receptor Mice Knockout Monocyte Purinergic receptor Articles Cell Biology Cyclic AMP-Dependent Protein Kinases Cell biology Mice Inbred C57BL medicine.anatomical_structure Macrophages Peritoneal Signal transduction Signal Transduction |
Zdroj: | American Journal of Physiology-Cell Physiology. 307:C571-C579 |
ISSN: | 1522-1563 0363-6143 |
DOI: | 10.1152/ajpcell.00087.2014 |
Popis: | A multitude of environmental signaling molecules influence monocyte and macrophage innate and adaptive immune responses, including ATP and prostanoids. Interestingly, purinergic (P2) and eicosanoid receptor signaling interact such that the activation of P2 receptors leads to prostanoid production, which can then interfere with P2Y-mediated macrophage migration. Recent studies suggest that blockade of 5-lipoxygenase (5-LOX) in macrophages can activate a permeation pathway involved in the influx of dye and the release of ATP. Here, we provide evidence that pannexin1 (Panx1) is a component of this pathway and present the intracellular signaling molecules linking the thromboxane (TP) receptor to Panx1-mediated dye influx and ATP release. Using pharmacological tools and transgenic mice deficient in Panx1, we show that two 5-LOX pathway inhibitors induce ATP release and influx of dye in a Panx1-dependent manner. Electrophysiological recordings performed in wild-type and Panx1-deficient macrophages confirmed that these 5-LOX pathway inhibitors activate currents characteristic of Panx1 channels. We found that the mechanism by which Panx1 channels are activated under this condition involves activation of the TP receptor that is mediated by the cAMP/PKA pathway. This is to our knowledge the first evidence for the involvement of Panx1 in the TP receptor signaling pathway. Future studies aimed to clarify the contribution of this TP-Panx1 signaling network to macrophage immune responses are likely to be important for targeting inflammatory and autoimmune diseases. |
Databáze: | OpenAIRE |
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