Аннотация
Calsequestrin is a high-capacity Ca-binding protein expressed inside
the sarcoplasmic reticulum (SR), an intracellular Ca release and
storage organelle in muscle. Mutations in the cardiac calsequestrin
gene (CSQ2) have been linked to arrhythmias and sudden death. We
have used Ca-imaging and patch-clamp methods in combination with
adenoviral gene transfer strategies to explore the function of CSQ2
in adult rat heart cells. By increasing or decreasing CSQ2 levels,
we showed that CSQ2 not only determines the Ca storage capacity of
the SR but also positively controls the amount of Ca released from
this organelle during excitation-contraction coupling. CSQ2 controls
Ca release by prolonging the duration of Ca fluxes through the SR
Ca-release sites. In addition, the dynamics of functional restitution
of Ca-release sites after Ca discharge were prolonged when CSQ2 levels
were elevated and accelerated in the presence of lowered CSQ2 protein
levels. Furthermore, profound disturbances in rhythmic Ca transients
in myocytes undergoing periodic electrical stimulation were observed
when CSQ2 levels were reduced. We conclude that CSQ2 is a key determinant
of the functional size and stability of SR Ca stores in cardiac muscle.
CSQ2 appears to exert its effects by influencing the local luminal
Ca concentration-dependent gating of the Ca-release channels and
by acting as both a reservoir and a sink for Ca in SR. The abnormal
restitution of Ca-release channels in the presence of reduced CSQ2
levels provides a plausible explanation for ventricular arrhythmia
associated with mutations of CSQ2.
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