title: Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function.
abstract: Current mechanisms of arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia (CPVT) require spontaneous Ca(2+) release via cardiac ryanodine receptor (RyR2) channels affected by gain-of-function mutations. Hence, hyperactive RyR2 channels eager to release Ca(2+) on their own appear as essential components of this arrhythmogenic scheme. This mechanism, therefore, appears inadequate to explain lethal arrhythmias in patients harboring RyR2 channels destabilized by loss-of-function mutations. We aimed to elucidate arrhythmia mechanisms in a RyR2-linked CPVT mutation (RyR2-A4860G) that depresses channel activity. Recombinant RyR2-A4860G protein was expressed equally as wild type (WT) RyR2, but channel activity was dramatically inhibited, as inferred by [(3)H]ryanodine binding and single channel recordings. Mice heterozygous for the RyR2-A4860G mutation (RyR2-A4860G(+/-)) exhibited basal bradycardia but no cardiac structural alterations; in contrast, no homozygotes were detected at birth, suggesting a lethal phenotype. Sympathetic stimulation elicited malignant arrhythmias in RyR2-A4860G(+/-) hearts, recapitulating the phenotype originally described in a human patient with the same mutation. In isoproterenol-stimulated ventricular myocytes, the RyR2-A4860G mutation decreased the peak of Ca(2+) release during systole, gradually overloading the sarcoplasmic reticulum with Ca(2+). The resultant Ca(2+) overload then randomly caused bursts of prolonged Ca(2+) release, activating electrogenic Na(+)-Ca(2+) exchanger activity and triggering early afterdepolarizations. The RyR2-A4860G mutation reveals novel pathways by which RyR2 channels engage sarcolemmal currents to produce life-threatening arrhythmias.
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Zhao
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Valdivia
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, Mexico; and.
authors.forename: Georgina B
authors.initials: GB
authors.lastname: Gurrola
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Powers
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: B Cicero
authors.initials: BC
authors.lastname: Willis
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: José
authors.identifier: http://orcid.org/0000-0003-0080-3500
authors.initials: J
authors.lastname: Jalife
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; hvaldiv@umich.edu.
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007545:Isoproterenol / Q000737:chemistry; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D007545:Isoproterenol; D002118:Calcium
keywords: CPVT; cardiac arrhythmias; heart; ryanodine receptor; sarcoplasmic reticulum