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(Circulation Research. 2002;91:181.)
© 2002 American Heart Association, Inc.

Editorials

Leaky "Feet" and Sudden Death

P.D. Allen

From the Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Department of Anesthesia, Harvard Medical School, Boston, Mass.

Correspondence to P.D. Allen, MD, PhD, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail allen@zeus.bwh.harvard.edu

Key Words: sarcoplasmic reticulum • ryanodine receptors • malignant hyperthermia • ventricular tachycardia • sudden death

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

Increases in intracellular Ca²⁺ are crucial signaling events in many cell types. The cardiac isoform of the (sarco)endoplasmic reticulum Ca²⁺ release channel or ryanodine receptor (RyR2) is an important component of this signaling pathway in a wide variety of both excitable (nerve, smooth muscle, and heart) and nonexcitable (parotid, pancreas, and adrenal medulla) cells and is a critical component of excitation-contraction coupling in the heart.^1,2 The absence of RyR2 in knockout mice leads to an early embryonic lethal phenotype because its function is essential for regulation of the intrinsic beating rate, and this early lethality has prevented studying its absence in other cell types.³

Unlike skeletal muscle, where excitation-contraction coupling is mediated through a mechanical coupling between its RyR isoform, RyR1, and the skeletal isoform of the sarcolemmal slow voltage-gated Ca²⁺ channel (dihydropyridine receptor, DHPR), in cardiac muscle, Ca²⁺ release through RyR2 is caused by the inward Ca²⁺ flux through the cardiac DHPR via Ca²⁺-induced Ca²⁺ release (CICR). It also appears that, at least in heart, RyR2 is part of a larger macromolecular complex containing phosphorylases, phosphatases, and the immunophilin FKBP12.6, which regulate the level of CICR.^4,5

Because of its large size (>200-kB gene, 15-kB mRNA), it is not surprising that the ryanodine receptor is a likely target for mutation. There are >30 reported missense mutations in the RyR1 gene that have been associated with alterations of Ca²⁺ homeostasis and are the cause of central core disease (CCD) and malignant hyperthermia (MH).^6–10 More recently, 11 missense mutations have been . . . [Full Text of this Article]