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Malignant Hyperthermia and Central Core Disease: Disorders of Ca2 Release Channels1

  • Julian Loke
    Affiliations
    Banting and Best Department of Medical Research (JL, DHM), University of Toronto, Toronto, Ontario, Canada

    MH Investigation Unit, Toronto Hospital, Department of Anaesthesia (JL), University of Toronto, Toronto, Ontario, Canada
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  • David H. MacLennan
    Correspondence
    Requests for reprints should be addressed to D.H. MacLennan, Banting & Best Department of Medical Research, C.H. Best Institute, University of Toronto, 112 College Street, Toronto, Ontario, Canada M5G 1L6
    Affiliations
    Banting and Best Department of Medical Research (JL, DHM), University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
      Muscle contraction and relaxation result from the interplay between two elaborate cellular structures and the small molecule, Ca2+, which cycles between them. The contractile elements are formed as short, repeating segments referred to as sarcomeres (
      • Huxley H.E.
      The mechanism of muscular contraction.
      ,
      • Huxley A.
      Muscular contraction.
      ). Within sarcomeres, longitudinally aligned, centrally located, thick filaments contain myosin, the adenosine triphosphate (ATP)-activated motor for the generation of contractile force (Figure 1). Thick filaments interdigitate between similarly aligned thin filaments that are anchored at either end of the sarcomere, but free in the center, forming bipolar arrays. The interaction between myosin molecules, oriented in a bipolar manner within thick filaments, and actin molecules in the two opposed thin filaments, results in shortening of the sarcomere as the thin filaments are drawn toward the center of the sarcomere. Relaxation results from release of the interaction between thin and thick filaments. In skeletal and cardiac muscle, the physical interactions between actin and myosin are possible only when Ca2+ is bound to a low molecular weight, high affinity Ca2+ binding protein, troponin C (
      • Zot A.S.
      • Potter J.D.
      Structural aspects of troponin-tropomyosin regulation of skeletal muscle contraction.
      ). Troponin C is located within a heterotrimeric, globular troponin complex, attached to filamentous tropomyosin, so that it forms a regulatory structure within the thin filament.
      Figure thumbnail GR1
      Figure 1Structures involved in excitation/contraction coupling in skeletal muscle. Four dihydropyridine receptor complexes in the transverse tubule abut the tetrameric ryanodine receptors in the junctional terminal cisternae of the sarcoplasmic reticulum. A voltage-dependent charge movement in the dihydropyridine receptor probably reflects a conformational change in the molecule that transmits an activation signal directly to the ryanodine receptor. The dihydropyridine receptor/ryanodine receptor interaction sites involve the II-III loop of the dihydropyridine receptor (see and may also involve the III-IV loop. The interaction sites in the ryanodine receptor are being defined. In the lumen of the sarcoplasmic reticulum, Ca2+ is stored as a complex with a high-capacity, low-affinity Ca2+-binding protein, calsequestrin, which probably interacts with the ryanodine receptor through its binding to triadin, a transmembrane protein with interaction sites for both calsequestrin and the ryanodine receptor (
      • Guo W.
      • Jorgensen A.O.
      • Jones L.R.
      • Campbell K.P.
      Biochemical characterization and molecular cloning of cardiac triadin.
      ,
      • Guo W.
      • Jorgensen A.O.
      • Campbell K.P.
      Triadin, a linker for calsequestrin and the ryanodine receptor.
      ). Ca2+ released from the sarcoplasmic reticulum is bound to troponin in the thin filaments of the sarcomere, permitting interaction between actin in the thin filaments and myosin in the thick filaments, leading to contraction. Removal of sarcoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum is accomplished by the action of Ca2+ pumps.
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