Enhanced Basal Activity of a Cardiac Ca <sup>2+</sup> Release Channel (Ryanodine Receptor) Mutant Associated With Ventricular Tachycardia and Sudden Death

DOI Web Site 被引用文献11件
  • Dawei Jiang
    From the Cardiovascular Research Group, Departments of Physiology and Biophysics and Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
  • Bailong Xiao
    From the Cardiovascular Research Group, Departments of Physiology and Biophysics and Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
  • Lin Zhang
    From the Cardiovascular Research Group, Departments of Physiology and Biophysics and Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
  • S.R. Wayne Chen
    From the Cardiovascular Research Group, Departments of Physiology and Biophysics and Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.

抄録

<jats:p> Mutations in the human cardiac Ca <jats:sup>2+</jats:sup> release channel (ryanodine receptor, RyR2) gene have recently been shown to cause effort-induced ventricular arrhythmias. However, the consequences of these disease-causing mutations in RyR2 channel function are unknown. In the present study, we characterized the properties of mutation R4496C of mouse RyR2, which is equivalent to a disease-causing human RyR2 mutation R4497C, by heterologous expression of the mutant in HEK293 cells. [ <jats:sup>3</jats:sup> H]ryanodine binding studies revealed that the R4496C mutation resulted in an increase in RyR2 channel activity in particular at low Ca <jats:sup>2+</jats:sup> concentrations. This increased basal channel activity remained sensitive to modulation by caffeine, ATP, Mg <jats:sup>2+</jats:sup> , and ruthenium red. In addition, the R4496C mutation enhanced the sensitivity of RyR2 to activation by Ca <jats:sup>2+</jats:sup> and by caffeine. Single-channel analysis showed that single R4496C mutant channels exhibited considerable channel openings at low Ca <jats:sup>2+</jats:sup> concentrations. HEK293 cells transfected with mutant R4496C displayed spontaneous Ca <jats:sup>2+</jats:sup> oscillations more frequently than cells transfected with wild-type RyR2. Substitution of a negatively charged glutamate for the positively charged R4496 (R4496E) further enhanced the basal channel activity, whereas replacement of R4496 by a positively charged lysine (R4496K) had no significant effect on the basal activity. These observations indicate that the charge and polarity at residue 4496 plays an essential role in RyR2 channel gating. Enhanced basal activity of RyR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia. </jats:p>

収録刊行物

  • Circulation Research

    Circulation Research 91 (3), 218-225, 2002-08-09

    Ovid Technologies (Wolters Kluwer Health)

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