The Ca²⁺ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Ryanodine receptors (RyR) are ion channels responsible for the release of Ca²⁺ from the sarco/endoplasmic reticulum and play a crucial role in the precise control of Ca²⁺ concentration in the cytosol. The detailed permeation mechanism of Ca²⁺ through RyR is still elusive. By using molecular dynamics simulations with a specially designed Ca²⁺ model, we show that multiple Ca²⁺ ions accumulate in the upper selectivity filter of RyR1, but only one Ca²⁺ can occupy and translocate in the narrow pore at a time, assisted by electrostatic repulsion from the Ca²⁺ within the upper selectivity filter. The Ca²⁺ 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 Ca²⁺ within the narrow pore, uncovering the basis underlying the high permeability and low selectivity of the RyR channels.