The Experts below are selected from a list of 108 Experts worldwide ranked by ideXlab platform
Sanjay S. Palnitkar - One of the best experts on this subject based on the ideXlab platform.
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identification of dantrolene binding sites in porcine skeletal muscle Sarcoplasmic reticulum
Journal of Biological Chemistry, 1995Co-Authors: Jerome Parness, Sanjay S. PalnitkarAbstract:Abstract Dantrolene, an intracellularly acting skeletal muscle relaxant, inhibits Ca release from the Sarcoplasmic reticulum during excitation-contraction coupling by an unknown mechanism. The drug is used to treat malignant hyperthermia, a genetic sensitivity to volatile anesthetics which results in the massive release of intracellular Ca from affected skeletal muscle. We hypothesize that determination of the site of action of dantrolene will lead to further understanding of the regulation of Sarcoplasmic reticulum calcium release. We report the identification of specific dantrolene binding sites in porcine skeletal muscle Sarcoplasmic reticulum using a rapid filtration binding assay for [3H]dantrolene. The binding isotherm in the heavy Sarcoplasmic reticulum fraction indicates a single binding site with a K of 277 ± 25 nM and a Bmax of 13.1 ± 1.5 pmol/mg of protein. Pharmacological specificity is characterized by inhibition of [3H]dantrolene binding with unlabeled dantrolene, or azumolene, a physiologically active congener, but not with aminodantrolene, which is physiologically inactive. Drug binding is maximal at pH 6.5-7.5, requires no Ca or Mg, and is inhibited by salt concentrations above 100 mM. [3H]Dantrolene binding is greatest in the Sarcoplasmic reticulum, which contains the ryanodine receptor, the primary calcium release channel. No binding is detected in the fractions enriched for sarcolemma or transverse tubules. We suggest that dantrolene inhibits calcium release from the Sarcoplasmic reticulum by either direct or indirect interaction with the ryanodine receptor.
Jerome Parness - One of the best experts on this subject based on the ideXlab platform.
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identification of dantrolene binding sites in porcine skeletal muscle Sarcoplasmic reticulum
Journal of Biological Chemistry, 1995Co-Authors: Jerome Parness, Sanjay S. PalnitkarAbstract:Abstract Dantrolene, an intracellularly acting skeletal muscle relaxant, inhibits Ca release from the Sarcoplasmic reticulum during excitation-contraction coupling by an unknown mechanism. The drug is used to treat malignant hyperthermia, a genetic sensitivity to volatile anesthetics which results in the massive release of intracellular Ca from affected skeletal muscle. We hypothesize that determination of the site of action of dantrolene will lead to further understanding of the regulation of Sarcoplasmic reticulum calcium release. We report the identification of specific dantrolene binding sites in porcine skeletal muscle Sarcoplasmic reticulum using a rapid filtration binding assay for [3H]dantrolene. The binding isotherm in the heavy Sarcoplasmic reticulum fraction indicates a single binding site with a K of 277 ± 25 nM and a Bmax of 13.1 ± 1.5 pmol/mg of protein. Pharmacological specificity is characterized by inhibition of [3H]dantrolene binding with unlabeled dantrolene, or azumolene, a physiologically active congener, but not with aminodantrolene, which is physiologically inactive. Drug binding is maximal at pH 6.5-7.5, requires no Ca or Mg, and is inhibited by salt concentrations above 100 mM. [3H]Dantrolene binding is greatest in the Sarcoplasmic reticulum, which contains the ryanodine receptor, the primary calcium release channel. No binding is detected in the fractions enriched for sarcolemma or transverse tubules. We suggest that dantrolene inhibits calcium release from the Sarcoplasmic reticulum by either direct or indirect interaction with the ryanodine receptor.
Roger J Hajjar - One of the best experts on this subject based on the ideXlab platform.
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altered Sarcoplasmic reticulum calcium cycling targets for heart failure therapy
Nature Reviews Cardiology, 2012Co-Authors: Changwon Kho, Ahyoung Lee, Roger J HajjarAbstract:Cardiac myocyte function is dependent on the synchronized movements of Ca2+ into and out of the cell, as well as between the cytosol and Sarcoplasmic reticulum. These movements determine cardiac rhythm and regulate excitation–contraction coupling. Ca2+ cycling is mediated by a number of critical Ca2+-handling proteins and transporters, such as L-type Ca2+ channels (LTCCs) and sodium/calcium exchangers in the sarcolemma, and Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), ryanodine receptors, and cardiac phospholamban in the Sarcoplasmic reticulum. The entry of Ca2+ into the cytosol through LTCCs activates the release of Ca2+ from the Sarcoplasmic reticulum through ryanodine receptor channels and initiates myocyte contraction, whereas SERCA2a and cardiac phospholamban have a key role in Sarcoplasmic reticulum Ca2+ sequesteration and myocyte relaxation. Excitation–contraction coupling is regulated by phosphorylation of Ca2+-handling proteins. Abnormalities in Sarcoplasmic reticulum Ca2+ cycling are hallmarks of heart failure and contribute to the pathophysiology and progression of this disease. Correcting impaired intracellular Ca2+ cycling is a promising new approach for the treatment of heart failure. Novel therapeutic strategies that enhance myocyte Ca2+ homeostasis could prevent and reverse adverse cardiac remodeling and improve clinical outcomes in patients with heart failure.
Sidney Fleischer - One of the best experts on this subject based on the ideXlab platform.
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[44] Reconstitution of functional Sarcoplasmic reticulum membrane vesicles
Methods in Enzymology, 2004Co-Authors: Gerhard Meissner, Sidney FleischerAbstract:Publisher Summary This chapter describes the dissociation and reconstitution of functional Sarcoplasmic reticulum vesicles, i.e., those that are again capable of energized Ca 2+ uptake and loading. Purified Sarcoplasmic reticulum vesicles are first disaggregated with deoxycholate and then reassembled by removal of the detergent using controlled dialysis. The reconstituted membrane vesicles have been reisolated and found to be of similar morphology, composition, and function to the original Sarcoplasmic reticulum. This procedure can also be used with slight modification for preparing functional membrane vesicles composed mainly of phospholipid and the Ca 2+ pump protein of Sarcoplasmic reticulum.
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[10] Functional and longitudinal Sarcoplasmic reticulum of heart muscle
Methods in Enzymology, 2004Co-Authors: Makoto Inui, Sherry Wang, Akitsugu Saito, Sidney FleischerAbstract:Publisher Summary This chapter focuses on the junctional and longitudinal Sarcoplasmic reticulum of heart muscle. In heart, muscle contraction is triggered by calcium, which derives from two sources: (1) Extracellular Ca 2+ enters via the plasmalemma during excitation; which then (2) induces Ca 2+ release from Sarcoplasmic reticulum (SR). This type of release is referred to as Ca 2+ -induced Ca 2+ release. In fast twitch skeletal muscle, essentially all of the Ca 2+ , which triggers muscle contraction derives from the Sarcoplasmic reticulum subsequent to depolarization at the plasmalemma/transverse tubule. This type of release is referred to as "depolarization-induced calcium release. '' In order to study the calcium release mechanism in skeletal muscle, a fraction of junctional terminal cisternae containing well-defined feet structures has been isolated. The feet structures in situ are involved in junctional association with the terminal cisternae to form the triad junction. The calcium release mechanism was found to be modulated by ryanodine at pharmacologically significant concentrations, and has been localized to the terminal cisternae of Sarcoplasmic reticulum.
Changwon Kho - One of the best experts on this subject based on the ideXlab platform.
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altered Sarcoplasmic reticulum calcium cycling targets for heart failure therapy
Nature Reviews Cardiology, 2012Co-Authors: Changwon Kho, Ahyoung Lee, Roger J HajjarAbstract:Cardiac myocyte function is dependent on the synchronized movements of Ca2+ into and out of the cell, as well as between the cytosol and Sarcoplasmic reticulum. These movements determine cardiac rhythm and regulate excitation–contraction coupling. Ca2+ cycling is mediated by a number of critical Ca2+-handling proteins and transporters, such as L-type Ca2+ channels (LTCCs) and sodium/calcium exchangers in the sarcolemma, and Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), ryanodine receptors, and cardiac phospholamban in the Sarcoplasmic reticulum. The entry of Ca2+ into the cytosol through LTCCs activates the release of Ca2+ from the Sarcoplasmic reticulum through ryanodine receptor channels and initiates myocyte contraction, whereas SERCA2a and cardiac phospholamban have a key role in Sarcoplasmic reticulum Ca2+ sequesteration and myocyte relaxation. Excitation–contraction coupling is regulated by phosphorylation of Ca2+-handling proteins. Abnormalities in Sarcoplasmic reticulum Ca2+ cycling are hallmarks of heart failure and contribute to the pathophysiology and progression of this disease. Correcting impaired intracellular Ca2+ cycling is a promising new approach for the treatment of heart failure. Novel therapeutic strategies that enhance myocyte Ca2+ homeostasis could prevent and reverse adverse cardiac remodeling and improve clinical outcomes in patients with heart failure.
