Ryanodine Receptor Mutations Associated With Stress-Induced Ventricular Tachycardia Mediate Increased Calcium Release in Stimulated Cardiomyocytes

DOI Web Site 被引用文献9件
  • Christopher H. George
    From the Wales Heart Research Institute, Department of Cardiology, University of Wales College of Medicine, Cardiff, UK.
  • Gemma V. Higgs
    From the Wales Heart Research Institute, Department of Cardiology, University of Wales College of Medicine, Cardiff, UK.
  • F. Anthony Lai
    From the Wales Heart Research Institute, Department of Cardiology, University of Wales College of Medicine, Cardiff, UK.

抄録

<jats:p> Ca <jats:sup>2+</jats:sup> release from the sarcoplasmic reticulum mediated by the cardiac ryanodine receptor (RyR2) is a fundamental event in cardiac muscle contraction. RyR2 mutations suggested to cause defective Ca <jats:sup>2+</jats:sup> channel function have recently been identified in catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD) affected individuals. We report expression of three CPVT-linked human RyR2 (hRyR2) mutations (S <jats:sup>2246</jats:sup> L, N <jats:sup>4104</jats:sup> K, and R <jats:sup>4497</jats:sup> C) in HL-1 cardiomyocytes displaying correct targeting to the endoplasmic reticulum. N <jats:sup>4104</jats:sup> K also localized to the Golgi apparatus. Phenotypic characteristics including intracellular Ca <jats:sup>2+</jats:sup> handling, proliferation, viability, RyR2:FKBP12.6 interaction, and beat rate in resting HL-1 cells expressing mutant hRyR2 were indistinguishable from wild-type (WT) hRyR2. However, Ca <jats:sup>2+</jats:sup> release was augmented in cells expressing mutant hRyR2 after RyR activation (caffeine and 4-chloro-m-cresol) or β-adrenergic stimulation (isoproterenol). RyR2:FKBP12.6 interaction remained intact after caffeine or 4-CMC activation, but was dramatically disrupted by isoproterenol or forskolin, an activator of adenylate cyclase. Isoproterenol and forskolin elevated cyclic-AMP to similar magnitudes in all cells and were associated with equivalent hyperphosphorylation of mutant and WT hRyR2. CPVT-linked mutations in hRyR2 did not alter resting cardiomyocyte phenotype but mediated augmented Ca <jats:sup>2+</jats:sup> release on RyR-agonist or β-AR stimulation. Furthermore, equivalent interaction between mutant and WT hRyR2 and FKBP12.6 was demonstrated. </jats:p>

収録刊行物

  • Circulation Research

    Circulation Research 93 (6), 531-540, 2003-09-19

    Ovid Technologies (Wolters Kluwer Health)

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