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

Aihua Zhang, Hua Yu, Chunhong Liu, Chen Song

Nature communications 2020 Feb 17

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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.

Citation

Aihua Zhang, Hua Yu, Chunhong Liu, Chen Song. The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model. Nature communications. 2020 Feb 17;11(1):922