title: Ruthenium red modifies the cardiac and skeletal muscle Ca(2+) release channels (ryanodine receptors) by multiple mechanisms.
abstract: The effects of ruthenium red (RR) on the skeletal and cardiac muscle ryanodine receptors (RyRs) were studied in vesicle-Ca(2+) flux, [(3)H]ryanodine binding, and single channel measurements. In vesicle-Ca(2+) flux measurements, RR was more effective in inhibiting RyRs at 0.2 microM than 20 microM free Ca(2+). [(3)H]Ryanodine binding measurements suggested noncompetitive interactions between RR inhibition and Ca(2+) regulatory sites of RyRs. In symmetric 0.25 M KCl with 10-20 microM cytosolic Ca(2+), cytosolic RR decreased single channel activities at positive and negative holding potentials. In close to fully activated skeletal (20 microM Ca(2+) + 2 mM ATP) and cardiac (200 microM Ca(2+)) RyRs, cytosolic RR induced a predominant subconductance at a positive but not negative holding potential. Lumenal RR induced a major subconductance in cardiac RyR at negative but not positive holding potentials and several subconductances in skeletal RyR. The RR-related subconductances of cardiac RyR showed a nonlinear voltage dependence, and more than one RR molecule appeared to be involved in their formation. Cytosolic and lumenal RR also induced subconductances in Ca(2+)-conducting skeletal and cardiac RyRs recorded at 0 mV holding potential. These results suggest that RR inhibits RyRs and induces subconductances by binding to cytosolic and lumenal sites of skeletal and cardiac RyRs.
authors.affiliation: Department of Biochemistry, University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: A
authors.initials: A
authors.lastname: Tripathy
authors.forename: D A
authors.initials: DA
authors.lastname: Pasek
authors.forename: G
authors.initials: G
authors.lastname: Meissner
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D004553:Electric Conductivity; D004594:Electrophysiology; D007700:Kinetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011510:Proteolipids / Q000378:metabolism; D011817:Rabbits; D012430:Ruthenium Red / Q000494:pharmacology*; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D011510:Proteolipids; D019837:Ryanodine Receptor Calcium Release Channel; C020485:proteoliposomes; D012430:Ruthenium Red; D012433:Ryanodine; D002118:Calcium