Abstract
Mutations in Ca$^2+$ -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 Ca$^2+$ release channel
known as the ryanodine receptor type 2 (RyR2). RyR2 mutations cause
"leaky" channels, resulting in diastolic Ca$^2+$ leak from the
sarcoplasmic reticulum (SR) that can trigger fatal cardiac arrhythmias
during stress. In this issue of the JCI, Song et al. show that mutations
in the SR Ca$^2+$-binding protein calsequestrin 2 (CASQ2) in
mice result not only in reduced CASQ2 expression but also in a surprising,
compensatory elevation in expression of both the Ca$^2+$-binding
protein calreticulin and RyR2, culminating in premature Ca$^2+$
release from cardiac myocytes and stress-induced arrhythmia (see
the related article beginning on page 1814). In the context of these
findings and other recent reports studying CASQ2 mutations, we discuss
how CASQ2 influences the properties of Ca$^2+$-dependent regulation
of RyR2 and how this contributes to cardiac arrhythmogenesis.
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