title: The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury.
abstract: Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemia-reperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3β might have a role in the Ca(2+) transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3β protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3β specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP3Rs) Ca(2+) channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3β decreased protein interaction of IP3R with the Ca(2+) channeling complex, impaired SR/ER Ca(2+) release and reduced the histamine-stimulated Ca(2+) exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3β activity and IP3R phosphorylation, which leads to enhanced transfer of Ca(2+) from SR/ER to mitochondria. Inhibition of GSK3β at reperfusion reduced both IP3R phosphorylation and SR/ER Ca(2+) release, which consequently diminished both cytosolic and mitochondrial Ca(2+) concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3β at reperfusion diminishes Ca(2+) leak from IP3R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca(2+) overload and subsequent cell death.
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.|Department of Medicine, Center for Translational Medicine, Sidney Kimmel College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: L
authors.initials: L
authors.lastname: Gomez
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: P-A
authors.initials: PA
authors.lastname: Thiebaut
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: M
authors.initials: M
authors.lastname: Paillard
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: S
authors.initials: S
authors.lastname: Ducreux
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: M
authors.initials: M
authors.lastname: Abrial
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: C
authors.initials: C
authors.lastname: Crola Da Silva
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: A
authors.initials: A
authors.lastname: Durand
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: M R
authors.initials: MR
authors.lastname: Alam
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: F
authors.initials: F
authors.lastname: Van Coppenolle
authors.affiliation: Hospices Civils de Lyon, Hôpital Louis Pradel, Service d'Explorations Fonctionnelles, Cardiovasculaires and CIC de Lyon, Lyon 69394, France.
authors.forename: S-S
authors.initials: SS
authors.lastname: Sheu
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.|Hospices Civils de Lyon, Hôpital Louis Pradel, Service d'Explorations Fonctionnelles, Cardiovasculaires and CIC de Lyon, Lyon 69394, France.
authors.forename: M
authors.initials: M
authors.lastname: Ovize
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D002118:Calcium