Calsequestrin: more than 'only' a luminal Ca2+ buffer inside the sarcoplasmic reticulum

In striated muscle, the sarcoplasmic reticulum (SR) Ca2+ release/ryanodine receptor (RyR) channel provides the pathway through which stored Ca2+ is re leased into the myoplasm during excitation-contraction coupling. Various lu minal Ca2+-binding proteins are responsible for maintaining the free [Ca2+] at 10(-3)-10(-4) M in the SR lumen; in skeletal-muscle SR, it is mainly ca lsequestrin. Here we show that, depending on its phosphorylation state, cal sequestrin selectively controls the RyR channel activity at 1 mM free lumin al [Ca2+]. Calsequestrin exclusively in the dephosphorylated state enhanced the open probability by approx. 5-fold with a Hill coefficient (h) of 3.3, and increased the mean open time by about 2-fold, i.e. solely dephosphoryl ated calsequestrin regulates Ca2+ release from the SR. Because calsequestri n has been found to occur mainly in the phosphorylated state in the skeleta l-muscle SR for the regulation of RyR channel activity, the dephosphorylati on of calsequestrin would appear to be a quintessential physiological event .