The Ca(2+) permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Ryanodine receptors (RyR) are ion channels responsible for the release of Ca(2+) from the sarco/endoplasmic reticulum and play a crucial role in the precise control of Ca(2+) concentration in the cytosol. The detailed permeation mechanism of Ca(2+) through RyR is still elusive. By using molecular dynamics simulations with a specially designed Ca(2+) model, we show that multiple Ca(2+) ions accumulate in the upper selectivity filter of RyR1, but only one Ca(2+) can occupy and translocate in the narrow pore at a time, assisted by electrostatic repulsion from the Ca(2+) within the upper selectivity filter. The Ca(2+) is nearly fully hydrated with the first solvation shell intact during the whole permeation process. These results suggest a remote knock-on permeation mechanism and one-at-a-time occupation pattern for the hydrated Ca(2+) within the narrow pore, uncovering the basis underlying the high permeability and low selectivity of the RyR channels.