Fig. 1

SERCA catalytic cycle. a SERCA pumps Ca²⁺ from the cytoplasm to the endoplasmic reticulum (ER) to create an ion gradient of ~ 10,000-fold across the cell membranes. During the catalytic cycle the Ca²⁺-ATPase switches between diverse oriented structures (E₁ and E₂) characterized by a different affinity for Ca²⁺ ions. The enzymatic transition between conformations catalyzes ATP in a stoichiometric ratio with Ca²⁺ of 1:2. E₁ binds two molecules of cytoplasmic Ca²⁺ (2Ca²⁺E₁, top right) and hydrolyzes one molecule of ATP to induce the high energy state of SERCA (E₁ ~ P). Following the decay in ADP, E₂ ~ P releases Ca²⁺ in the ER lumen. The cycle is closed and reopened along with the dephosphorylation of SERCA. b Thapsigargin (or other SERCA inhibitors) locks SERCA in the ground E₂ state (“dead-end”) preventing Ca²⁺ binding and ATP hydrolysis. Thapsigargin blockade causes a continuum leakage of Ca²⁺ from the ER to the cytosol reverting the physiological polarization of Ca²⁺ across these two compartments