title: Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.
abstract: BACKGROUND
  Familial polymorphic ventricular tachycardia (FPVT) is characterized by exercise-induced arrhythmias and sudden cardiac death due to missense mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release channel required for excitation-contraction coupling in the heart.
  
  
  RESULTS
  Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur in Finnish families, result in similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the fight-or-flight stress response. We simulated the effects of exercise on mutant RyR2 channels using protein kinase A (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of-function defect consistent with leaky Ca2+ release channels and a significant rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50). Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to RyR2 and normalized channel function.
  
  
  CONCLUSIONS
  Sympathetic activation during exercise induces ventricular arrhythmias above a threshold heart rate in RyR2 mutation carriers. Simulating the downstream effects of the sympathetic activation by PKA phosphorylation of RyR2 channels containing these FPVT missense mutations produced a consistent gain-of-function defect. RyR2 function and calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients.
authors.affiliation: Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 W. 168th St, P&S 9-401, Box 65, New York, NY 10032, USA.
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Laitinen
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.forename: Shi-Xiang
authors.initials: SX
authors.lastname: Deng
authors.forename: Zhenzhuang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Donald W
authors.initials: DW
authors.lastname: Landry
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000453:epidemiology*; D005387:Finland / Q000453:epidemiology; D005799:Genes, Dominant; D006801:Humans; D020128:Inhibitory Concentration 50; D017136:Ion Transport / Q000235:genetics; D008274:Magnesium / Q000008:administration & dosage / Q000494:pharmacology; D008875:Middle Aged; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D005082:Physical Exertion; D017354:Point Mutation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017180:Tachycardia, Ventricular / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C109183:K201 compound; D017868:Cyclic AMP-Dependent Protein Kinases; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D008274:Magnesium; D002118:Calcium