title: S100A1 decreases calcium spark frequency and alters their spatial characteristics in permeabilized adult ventricular cardiomyocytes.
abstract: S100A1, a Ca2+-sensor protein of the EF-hand type, exerts positive inotropic effects in the heart via enhanced cardiac ryanodine receptor (RyR2) activity. Here we report that S100A1 protein (0.1microM) interacts with the RyR2 in resting permeabilized cardiomyocytes at free Ca2+-levels comparable to diastolic Ca2+-concentrations ( approximately 150nM). Alterations of RyR2 function due to S100A1 binding was assessed via analysis of Ca2+-spark characteristics. Ca2+-spark frequency, amplitude and duration were all reduced upon perfusion with 0.1microM S100A1 protein by 38%, 14% and 18%, respectively. Most likely, these effects were conveyed through the S100A1 C-terminus (S100A1-ct; amino acids 75-94) as the corresponding S100A1-ct peptide (0.1microM) inhibited S100A1 protein binding to the RyR2 and similarly attenuated frequency, amplitude and duration of Ca2+-sparks by 52%, 8% and 26%, respectively. Accordingly, the sarcoplasmic reticulum (SR) Ca2+-content was slightly increased but the stoichiometry of other accessory RyR2 modulators (sorcin/FKBP12.6) remained unaltered by S100A1. Hence, we propose S100A1 as a novel inhibitory modulator of RyR2 function at diastolic Ca2+-concentrations in rabbit ventricular cardiomyocytes.
authors.affiliation: Department of Internal Medicine III, Laboratory for Cardiac Stem Cell and Gene Therapy, Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Loughrey
authors.forename: Niall
authors.initials: N
authors.lastname: Macquaide
authors.forename: Andrew
authors.initials: A
authors.lastname: Remppis
authors.forename: Brent R
authors.initials: BR
authors.lastname: DeGeorge
authors.forename: Frederic V
authors.initials: FV
authors.lastname: Wegner
authors.forename: Oliver
authors.initials: O
authors.lastname: Friedrich
authors.forename: Rainer H A
authors.initials: RH
authors.lastname: Fink
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling; D002478:Cells, Cultured; D003971:Diastole; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism* / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; D002118:Calcium