Ca regulation of connexin 43 hemichannels in C6 glioma and glial cells |
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Authors: | Elke De Vuyst Nan Wang Elke Decrock Marijke De Bock Mathieu Vinken Marijke Van Moorhem Charles Lai Maxime Culot Vera Rogiers Romeo Cecchelli Christian C Naus W Howard Evans Luc Leybaert |
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Institution: | 1. Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium;2. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States;3. Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil;4. Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium;5. Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium;6. Department of Pathology, St. David''s North Austin Medical Center, Austin, United States;1. Department of Molecular Oncology, Institute for Cancer Research, University of Oslo, NO-0424 Oslo, Norway;2. STIM Laboratory ERL 7368 CNRS – Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers 86073, France;3. Translational Molecular Pathology, Vall d''Hebron Institute of Research (VHIR), Autonomous University of Barcelona, CIBERONC, 08035 Barcelona, Spain;4. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, NO-0424 Oslo, Norway;1. Buchanan Ocular Therapeutics Unit, Department of Ophthalmology and the New Zealand National Eye Centre, University of Auckland, New Zealand;2. Department of Ophthalmology and the New Zealand National Eye Centre, University of Auckland, New Zealand;3. Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, University of Auckland, New Zealand;4. School of Optometry and Vision Science and the New Zealand National Eye Centre, University of Auckland, New Zealand |
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Abstract: | Connexin hemichannels have a low open probability under normal conditions but open in response to various stimuli, forming a release pathway for small paracrine messengers. We investigated hemichannel-mediated ATP responses triggered by changes of intracellular Ca2+ (Ca2+]i) in Cx43 expressing glioma cells and primary glial cells. The involvement of hemichannels was confirmed with gja1 gene-silencing and exclusion of other release mechanisms. Hemichannel responses were triggered when Ca2+]i was in the 500 nM range but the responses disappeared with larger Ca2+]i transients. Ca2+-triggered responses induced by A23187 and glutamate activated a signaling cascade that involved calmodulin (CaM), CaM-dependent kinase II, p38 mitogen activated kinase, phospholipase A2, arachidonic acid (AA), lipoxygenases, cyclo-oxygenases, reactive oxygen species, nitric oxide and depolarization. Hemichannel responses were also triggered by activation of CaM with a Ca2+-like peptide or exogenous application of AA, and the cascade was furthermore operational in primary glial cells isolated from rat cortex. In addition, several positive feed-back loops contributed to amplify the responses. We conclude that an elevation of Ca2+]i triggers hemichannel opening, not by a direct action of Ca2+ on hemichannels but via multiple intermediate signaling steps that are adjoined by distinct signaling mechanisms activated by high Ca2+]i and acting to restrain cellular ATP loss. |
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Keywords: | Calcium Glutamate Connexon Eicosanoids Gliotransmitter Glial cells |
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