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(Circulation. 2002;106:8.)
© 2002 American Heart Association, Inc.

Editorial

Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death

Andrew R. Marks, MD

From the Center for Molecular Cardiology, Department of Pharmacology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to Andrew R. Marks, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians & Surgeons, Rm 9-40, 630 W 168th St, New York, NY 10032. E-mail arm42@columbia.edu

Key Words: Editorials • death, sudden • sarcoplasmic reticulum • genetics • calcium

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The cardiac ryanodine receptor (RyR2) is the major calcium (Ca²⁺) release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes. During excitation-contraction, coupling intracellular Ca²⁺ stored in the SR is released via RyR2 to activate muscle contraction. In the heart, excitation-contraction coupling is activated by Ca²⁺ influx via the L-type Ca²⁺ channel that activates RyR2, a process referred to as Ca²⁺-induced Ca²⁺ release.^1,2 The cardiac muscle RyR2 and its homologue, the skeletal muscle RyR1, are macromolecular complexes that include four 565-kDa RyR1 or RyR2, four FKBP12 or FKBP12.6 (12-kDa peptidyl-prolyl isomerases that are required for normal gating of the channels), as well as cAMP-dependent kinase (PKA), phosphatases, and their targeting proteins.^3–5 One key role for the macromolecular signaling complex is to modulate channel function in response to activation of the sympathetic nervous system (ie, the classic "fight-or-flight" stress response).^5,6

See p 69

In the past year, three groups have independently discovered at least 21 mutations in RyR2 (Figure) that are linked to stress-induced sudden cardiac death.^7–9 To date, RyR2 mutations have been associated with 2 forms of sudden cardiac death (SCD): (1) catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic ventricular tachycardia (FPVT), and (2) arrhythmogenic right ventricular dysplasia type 2 (ARVD2).

View larger version (20K): [in this window] [in a new window]   Exercise-induced SCD-linked RyR2 mutations. Locations of SCD mutations in human RyR2 compared with MH/CCD regions of RyR1 and known regulatory domains of the channel. Eleven reported SCD-linked RyR2 mutations7–9 cluster in three regions homologous to three MH/CCD regions.30,31 Common polymorphisms are indicated by italics. The . . . [Full Text of this Article]

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