A co-operative knock-on mechanism underpins Ca 2+ -selective cation permeation in TRPV channels

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The selective exchange of ions across cellular membranes is a vital biological process. Ca 2+ -mediated signalling is implicated in a broad array of physiological processes in cells, whilst elevated intracellular concentrations of Ca 2+ are cytotoxic. Due to the significance of this cation, strict Ca 2+ concentration gradients are maintained across the plasma and organelle membranes. Therefore, Ca 2+ signalling relies on permeation through selective ion channels that control the flux of Ca 2+ ions. A key family of Ca 2+ -permeable membrane channels are the polymodal signal-detecting Transient Receptor Potential (TRP) ion channels. TRP channels are activated by a wide variety of cues including temperature, small molecules, transmembrane voltage and mechanical stimuli. Whilst most members of this family permeate a broad range of cations non-selectively, TRPV5 and TRPV6 are unique due to their strong Ca 2+ -selectivity. Here, we address the question of how some members of the TRPV subfamily show a high degree of Ca 2+ -selectivity whilst others conduct a wider spectrum of cations. We present results from all-atom molecular dynamics simulations of ion permeation through two Ca 2+ -selective and two non-selective TRPV channels. Using a new method to quantify permeation co-operativity based on mutual information, we show that Ca 2+ -selective TRPV channel permeation occurs by a three binding site knock-on mechanism, whereas a two binding site knock-on mechanism is observed in non-selective TRPV channels. Each of the ion binding sites involved displayed greater affinity for Ca 2+ over Na + . As such, our results suggest that coupling to an extra binding site in the Ca 2+ -selective TRPV channels underpins their increased selectivity for Ca 2+ over Na + ions. Furthermore, analysis of all available TRPV channel structures shows that the selectivity filter entrance region is wider for the non-selective TRPV channels, slightly destabilising ion binding at this site, which is likely to underlie mechanistic decoupling.

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