The canonical transient receptor potential 6 (TRPC6) channel is sensitive to extracellular pH in mouse platelets |
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| Affiliation: | 1. School of Medicine and Medical Science, University College Dublin, Ireland;2. Conway Institute, University College Dublin, Ireland;3. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands;4. School of Biochemistry & Biomedical Diagnostics Institute, Dublin City University, Ireland;5. Department of Haematology, Rotunda Hospital, Dublin, Ireland;6. Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland;7. Department of Neonatology, Rotunda Hospital, Dublin, Ireland;1. Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA;2. CompleGen, Inc., 1124 Columbia Street, Seattle, WA 98104, USA;3. Department of Pharmacology and Toxicology, Michigan State University, 1355 Bogue St./B440 Life Sciences, East Lansing, MI 48824, USA;4. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, 900 S Ashland, Chicago, IL 60607, USA |
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| Abstract: | The canonical transient receptor potential-6 (TRPC6) is a receptor-activated non-selective Ca2 + channel regulated by a variety of modulators such as diacylglycerol, Ca2 +/calmodulin or phosphorylation. The present study is aimed to investigate whether different situations, such as acidic pH, exposure to reactive oxygen species (ROS) or hypoxic-like conditions modulate TRPC6 channel function. Here we show normal aggregation and Ca2 + mobilization stimulated by thrombin in TRPC6 KO platelets; however, OAG (1-oleoyl-2-acetyl-sn-glycerol)-evoked Ca2 + entry was attenuated in the absence of TRPC6. Exposure of mouse platelets to acidic pH resulted in abolishment of thrombin-evoked aggregation and attenuated platelet aggregation induced by thapsigargin (TG) or OAG. Both OAG-induced Ca2 + entry and platelet aggregation were greatly attenuated in cells expressing TRPC6 channels. Exposure of platelets to H2O2 or deferoxamine did not clearly alter thrombin, TG or OAG-induced platelet aggregation. Our results indicate that TRPC6 is sensitive to acidic pH but not to exposure to ROS or hypoxic-like conditions, which might be involved in the pathogenesis of the altered platelet responsiveness to DAG-generating agonists in disorders associated to acidic pH. |
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