title: Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca2+ uptake through the mitochondrial ryanodine receptor in cardiac myocytes.
abstract: Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms.
  
  
  
  We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca(2+ )elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca(2+ )uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca(2+ )(Ca(2 +) m) but only ET-1 led to an increase in ATP concentration. ET-1-induced effects were prevented by cell treatment with the IP3 antagonist 2-aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP3 chelating protein (IP3 sponge). Furthermore, ET-1-induced mitochondrial Ca(2+) uptake was insensitive to the mitochondrial Ca(2+ )uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real-time polymerase chain reaction, we detected the presence of all three isoforms of IP3Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors.
  
  
  
  Stimulation of IP3Rs with ET-1 induces Ca(2+ )release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production.
authors: Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany Comprehensive Heart Failure Center, University of Würzburg, Straubmühlweg 2a, 97078 Würzburg, Germany seidlmayer_l@ukw.de.
authors: Lea K
authors: LK
authors: Seidlmayer
authors: Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany.
authors: Johannes
authors: J
authors: Kuhn
authors: Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany.
authors: Annette
authors: A
authors: Berbner
authors: Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany.
authors: Paula-Anahi
authors: PA
authors: Arias-Loza
authors: Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany.
authors: Tatjana
authors: T
authors: Williams
authors: Comprehensive Heart Failure Center, University of Würzburg, Straubmühlweg 2a, 97078 Würzburg, Germany.
authors: Mathias
authors: M
authors: Kaspar
authors: Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany.
authors: Martin
authors: M
authors: Czolbe
authors: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, MLC 7020 Cincinnati, OH 45229, USA.
authors: Jennifer Q
authors: JQ
authors: Kwong
authors: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, MLC 7020 Cincinnati, OH 45229, USA.
authors: Jeffery D
authors: JD
authors: Molkentin
authors: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.
authors: Katrin Gertrud
authors: KG
authors: Heinze
authors: Department of Pharmacology, School of Medicine, University of California Davis, 451 E. Health Sciences Drive, Genome and Biomedical Sciences Facility, Davis, CA 95616, USA.
authors: Elena N
authors: EN
authors: Dedkova
authors: Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany Comprehensive Heart Failure Center, University of Würzburg, Straubmühlweg 2a, 97078 Würzburg, Germany Medizinische Hochschule Brandenburg, Campus Klinikum Brandenburg/Havel, Abteilung für Kardiologie und Pneumologie, Hochstr. 29, 14770 Brandenburg an der Havel, Germany.
authors: Oliver
authors: O
authors: Ritter
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000494:pharmacology; D005838:Genotype; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D019332:Endothelin-1; C582634:ITPR3 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; C580990:Ip3r2 protein, mouse; C025389:Itpr1 protein, mouse; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; C000592747:ryanodine receptor 1, mouse; C000592748:ryanodine receptor 2. mouse; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D007545:Isoproterenol
keywords: Dantrolene; IP3 sponge; Inositol 1,4,5-trisphosphate; Mitochondrial Ca uniporter; Mitochondrial ryanodine receptor