From Selective Permeation to Physiology in Potassium Channels

Figures

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  Figure 1.. The potassium channel pore domain. (A) Cartoon representation of canonical potassium channel pore domain with the selectivity filter (SF) highlighted in pink, the pore helix in green, and the helix bundle crossing (HBC) gate in blue. (B) Multiple sequence alignment of representative potassium channel sequences that are covered in this review.

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  Figure 2.. Ion occupancy of selectivity filters (SFs). (A) The canonical K+ channel TVGYG SF with binding sites indicated. (B) Schematic description of SF occupancy in the direct knock-on permeation mechanism, in which direct ion-ion contacts facilitate efficient permeation. (C) Selectivity filter occupancy states in the soft knock-on permeation mechanism, in which K+ ions are separated by water molecules. (D) Na+ occupancy in the K+ channel SF, with Na+ ions bound in-plane with oxygen atoms at S1 and S4. (E) Selectivity filter of the NavMs sodium channel with solvated sodium bound.

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  Figure 3.. Selectivity filter (SF) occupancy in KcsA mutants. X-ray structures of wild type and mutant KcsA SFs with electron density and occupancy of the S1-S4 binding sites indicated. Potassium ions are shown as purple spheres, while water molecules are represented by red dots. PDB IDs: WT 5VK6, G77A 6NFU, and T75A 6BY3. Adapted from Mironenko et al.31.

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  Figure 4.. Potassium channel selectivity filter (SF) conformations in different functional states. Snapshots of the SF backbone of 2 opposing chains taken from MD simulations to illustrate the distinct hypothesized or identified states discussed in the text: (A) ordered, conductive state; (B) locked, inactivated state; (C) dilated, inactivated state; (D) dilated state, suggested as intermediate to the fully inactivated dilated state; (E) collapsed, inactivated state.

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  Figure 5.. Selectivity filter (SF) dynamics revealed by smFRET. (A) FRET efficiency between 2 fluorophores placed immediately above the SF. The FRET histogram shifts to higher efficiency, implying a more constrained SF conformation, as K+ replaces Na+ in the bathing solution. (B) Schematic indication of SF conformational changes reflecting high (H), medium (M), and low (L) FRET efficiencies, with the preferred conformations shifting from dilated to constrained, ion, as K+ replaces Na+. Adapted from Wang et al.88

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  Figure 6.. Multiple modes of potassium channel selectivity filter (SF) modulation. Central cartoon diagram shows the approximate locations of different channel modulators discussed in the text. Two opposing subunits are only shown in white for the pore domain and in gray for the voltage sensing domains (of Kv channels). Each modulator is represented in different colors, and the modulators are depicted in the same color in each zoomed-in structural diagram. (A) Inhibitory A0194009G09 nanobody bound Kv1.3 structure (PDB:7SSZ);145 (B) Fab-shk bound Kv1.3 structure (PDB: 7SSV);145 (C) Predicted linoleic acid bound Kv7.1 structure from molecular dynamics simulation (MDS);138 (D). ML335 bound to TREK-1 structure (PDB:6CQ8),133 (E). Predicted BL-1249, an activator, interaction with TRAAK by MDS;131 (F). Norfluoxetine, an inhibitor, interacting with TREK-2 (PDB:4XDK).85