Calsequestrin depolymerizes when calcium is depleted in the sarcoplasmic reticulum of working muscle

Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E638-E647. doi: 10.1073/pnas.1620265114. Epub 2017 Jan 9.


Calsequestrin, the only known protein with cyclical storage and supply of calcium as main role, is proposed to have other functions, which remain unproven. Voluntary movement and the heart beat require this calcium flow to be massive and fast. How does calsequestrin do it? To bind large amounts of calcium in vitro, calsequestrin must polymerize and then depolymerize to release it. Does this rule apply inside the sarcoplasmic reticulum (SR) of a working cell? We answered using fluorescently tagged calsequestrin expressed in muscles of mice. By FRAP and imaging we monitored mobility of calsequestrin as [Ca2+] in the SR--measured with a calsequestrin-fused biosensor--was lowered. We found that calsequestrin is polymerized within the SR at rest and that it depolymerized as [Ca2+] went down: fully when calcium depletion was maximal (a condition achieved with an SR calcium channel opening drug) and partially when depletion was limited (a condition imposed by fatiguing stimulation, long-lasting depolarization, or low drug concentrations). With fluorescence and electron microscopic imaging we demonstrated massive movements of calsequestrin accompanied by drastic morphological SR changes in fully depleted cells. When cells were partially depleted no remodeling was found. The present results support the proposed role of calsequestrin in termination of calcium release by conformationally inducing closure of SR channels. A channel closing switch operated by calsequestrin depolymerization will limit depletion, thereby preventing full disassembly of the polymeric calsequestrin network and catastrophic structural changes in the SR.

Keywords: cardiac muscle; catecholaminergic polymorphic ventricular tachycardia; excitation/contraction coupling; muscle diseases; skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Calsequestrin / metabolism*
  • Mice
  • Muscle, Skeletal / metabolism*
  • Myocardium / metabolism
  • Sarcoplasmic Reticulum / metabolism*


  • Calcium Channels
  • Calsequestrin
  • Calcium