Deconstructing calsequestrin. Complex buffering in the calcium store of skeletal muscle

Since its discovery in 1971, calsequestrin has been recognized as the main Ca(2+) binding protein inside the sarcoplasmic reticulum (SR), the organelle that stores and upon demand mobilizes Ca(2+) for contractile activation of muscle. This article reviews the potential roles of calsequestrin in excitation-contraction coupling of skeletal muscle. It first considers the quantitative demands for a structure that binds Ca(2+) inside the SR in view of the amounts of the ion that must be mobilized to elicit muscle contraction. It briefly discusses existing evidence, largely gathered in cardiac muscle, of two roles for calsequestrin: as Ca(2+) reservoir and as modulator of the activity of Ca(2+) release channels, and then considers the results of an incipient body of work that manipulates the cellular endowment of calsequestrin. The observations include evidence that both the Ca(2+) buffering capacity of calsequestrin in solution and that of the SR in intact cells decay as the free Ca(2+) concentration is lowered. Together with puzzling observations of increase of Ca(2+) inside the SR, in cells or vesicular fractions, upon activation of Ca(2+) release, this is interpreted as evidence that the Ca(2+) buffering in the SR is non-linear, and is optimized for support of Ca(2+) release at the physiological levels of SR Ca(2+) concentration. Such non-linearity of buffering is qualitatively explained by a speculation that puts together ideas first proposed by others. The speculation pictures calsequestrin polymers as 'wires' that both bind Ca(2+) and efficiently deliver it near the release channels. In spite of the kinetic changes, the functional studies reveal that cells devoid of calsequestrin are still capable of releasing large amounts of Ca(2+) into the myoplasm, consistent with the long term viability and apparent good health of mice engineered for calsequestrin ablation. The experiments therefore suggest that other molecules are capable of providing sites for reversible binding of large amounts of Ca(2+) inside the sarcoplasmic reticulum.