title: Inhibitors of the 5-lipoxygenase pathway activate pannexin1 channels in macrophages via the thromboxane receptor.
abstract: 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.
authors: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto Nacional de Ciência e Tecnologia de Pesquisa Translacional em Saúde e Ambiente da Região Amazônica-INPeTAm, Rio de Janeiro, Brazil; and Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
authors: Hercules A
authors: HA
authors: da Silva-Souza
authors: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;
authors: Maria Nathália
authors: MN
authors: de Lira
authors: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
authors: Naman K
authors: NK
authors: Patel
authors: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
authors: David C
authors: DC
authors: Spray
authors: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto Nacional de Ciência e Tecnologia de Pesquisa Translacional em Saúde e Ambiente da Região Amazônica-INPeTAm, Rio de Janeiro, Brazil; and.
authors: Pedro Muanis
authors: PM
authors: Persechini
authors: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York eliana.scemes@einstein.yu.edu.
authors: Eliana
authors: E
authors: Scemes
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D017630:Connexins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017630:Connexins; D016859:Lipoxygenase Inhibitors; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D017482:Receptors, Thromboxane; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: ATP release; dye uptake; macrophages; pannexin; prostanoids