Abstract
Calsequestrin (CASQ2) is a high capacity Ca-binding protein expressed
inside the sarcoplasmic reticulum (SR). Mutations in the cardiac
calsequestrin gene (CASQ2) have been linked to arrhythmias and sudden
death induced by exercise and emotional stress. We have studied the
function of CASQ2 and the consequences of arrhythmogenic CASQ2 mutations
on intracellular Ca signalling using a combination of approaches
of reverse genetics and cellular physiology in adult cardiac myocytes.
We have found that CASQ2 is an essential determinant of the ability
of the SR to store and release Ca$^2+$ in cardiac muscle. CASQ2
serves as a reservoir for Ca$^2+$ that is readily accessible
for Ca$^2+$-induced Ca$^2+$ release (CICR) and also as an
active Ca$^2+$ buffer that modulates the local luminal Ca-dependent
closure of the SR Ca$^2+$ release channels. At the same time,
CASQ2 stabilizes the CICR process by slowing the functional recharging
of SR Ca$^2+$ stores. Abnormal restitution of the Ca$^2+$
release channels from a luminal Ca-dependent refractory state could
account for ventricular arrhythmias associated with mutations in
the CASQ2 gene.
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