title: FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.
abstract: Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca(2+) release and cardiac contractility. FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.
authors.affiliation: Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Fannie
authors.initials: F
authors.lastname: Huang
authors.forename: John A
authors.initials: JA
authors.lastname: Vest
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
authors.forename: Long Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Nora
authors.initials: N
authors.lastname: Rosemblit
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Mirella
authors.initials: M
authors.lastname: Memmi
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: W J
authors.initials: WJ
authors.lastname: Lederer
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D017079:Exercise Tolerance / Q000235:genetics*; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency* / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B