Selecting Ions by Size in a Calcium Channel: The Ryanodine Receptor Case Study

Abstract

Many calcium channels can distinguish between ions of the same charge but different size. For example, when cations are in direct competition with each other, the ryanodine receptor (RyR) calcium channel preferentially conducts smaller cations such as Li(+) and Na(+) over larger ones such as K(+) and Cs(+). Here, we analyze the physical basis for this preference using a previously established model of RyR permeation and selectivity. Like other calcium channels, RyR has four aspartate residues in its GGGIGDE selectivity filter. These aspartates have their terminal carboxyl group in the pore lumen, which take up much of the available space for permeating ions. We find that small ions are preferred by RyR because they can fit into this crowded environment more easily.

Gating machinery of InsP3R channels revealed by electron cryomicroscopy

“…At Phe2586, densities for the side chains are clearly visible and point towards the central axis, where they shape a pore of ~5Å in diameter, suggesting a non-conducting channel conformation given an effective diameter of the hydrated Ca 2+ (8–10 Å) 13 . Noteworthy, in this configuration the pore will also not be permissive for hydrated K + ions (6 Å) 14 . Equivalent hydrophobic constrictions have been identified in the structures of other channels 15–19 (Supplementary Discussion).…”

Is ryanodine receptor a calcium or magnesium channel? Roles of K+ and Mg2+ during Ca2+ release

“…The model we use in this paper [1, 2, 8–10] (which is described in Appendix A) has reproduced RyR current/voltage experiments in more than 160 different ionic conditions, including those of Kettlun et al [6]. It also predicted specific anomalous mole fraction effects and their concentration dependence before these were experimentally verified [1, 2, 8, 10]. The unusually broad experimental verification of this RyR permeation model lends substantial confidence to its predictions.…”

“…Among monovalents, smaller ones like Li + are favored over larger ones like Cs + [2]. To date, the model has accurately predicted RyR current in more than 160 different ionic concentrations (including of divalent and monovalent cation mixtures) over a wide range of applied voltages [1, 2, 8–10]. To stringently evaluate this model, several a priori model predictions were made and subsequently experimentally verified without the predictions known to the experimentalists [1, 2, 8–10].…”

“…These predictions include the reduction in divalent cation selectivity at high divalent concentrations (Fig. 3), net current in mixtures of three monovalent cations over a wide range of concentrations [10], and anomalous mole fraction effects in mixtures of Na + and Cs + [1] and in mixtures of Ca 2+ and Li + , Na + , K + , or Cs + [2, 8], including their concentration and voltage behavior [8]. This unprecedented level of RyR permeation model validation instills substantial confidence that the ionic currents calculated by this model accurately reflect those carried by the real channel.…”

Muscling in on the ryanodine receptor

“…The structures provide a high-resolution view of the pore, enabling identification of specific features that regulate ion selectivity and gating 13 . It is reassuring to see several features common with other cation channels, namely TRP, potassium and sodium channels.…”