In the normal heart, the cycling of intracellular calcium in cardiac muscle cells is critical to the heart?s mechanical contraction and relaxation. Mutations in calcium-handling proteins in the heart have been linked to exercise-induced sudden cardiac death.
The best characterized of these have been mutations in the cardiac calcium release channel known as the ryanodine receptor (RyR2), which result in calcium ?leak? from the sarcoplasmic reticulum (SR) that can trigger fatal cardiac arrhythmias during stress.
In the July 2 issue of the Journal of Clinical Investigation, Jonathan Seidman and colleagues from Harvard Medical School show that mutations in another SR calcium-binding protein, calsequestrin 2 (CASQ2), in mice result not only in reduced CASQ2 expression, but also in a surprising compensatory elevation in both the calcium-binding protein calreticulin and RyR2, culminating in premature release of calcium from cardiac muscle cells, causing stress-induced arrhythmia.
An accompanying commentary by Jonathan Lederer and colleagues from University of Maryland and Ohio State University discusses the pathways involved in calcium signaling in the heart. Mutations in RyR2 or CASQ2 may provide therapeutic targets for the treatment of inherited cardiac arrhythmias.
TITLE: Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia