Dilation of ion selectivity filters in cation channels

Abstract

Ion channels establish the voltage gradient across cellular membranes by providing aqueous pathways for ions to selectively diffuse down their concentration gradients. The selectivity of any given channel for its favored ions has conventionally been viewed as a stable property, and in many cation channels, it is determined by an ion-selectivity filter within the external end of the ion-permeation pathway. In several instances, including voltage-activated K⁺ (Kv) channels, ATP-activated P2X receptor channels, and transient receptor potential (TRP) channels, the ion-permeation pathways have been proposed to dilate in response to persistent activation, dynamically altering ion permeation. Here, we discuss evidence for dynamic ion selectivity, examples where ion selectivity filters exhibit structural plasticity, and opportunities to fill gaps in our current understanding.

Keywords: ATP-activated P2X receptor channels; Kv channels; TRP channels; ion selectivity.

Figure 1 |. Conformational changes in the ion selectivity filter of the KcsA K⁺ channel.

A) External view of KcsA channel structure in high K⁺ (PDBID: 1K4C) showing tetrameric ion conducting pore. B) Side view of two opposing KcsA channel subunits in high K⁺ (PDBID: 1K4C) with HOLE plot of the central ion permeation pathway illustrated in gray spheres. Two Fabs associated with these opposing subunits are shown in gray. C) Expanded view of the ion selectivity filter with two opposing subunits of KcsA in a conducting conformation obtained in high K⁺ (PDBID: 1K4C), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black. A key hydrogen bond between W67 and D80 is shown with yellow dashed lines. Water molecules are shown as red spheres and K⁺ ions are shown as purple spheres. D) Expanded view of the ion selectivity filter with two opposing subunits of KcsA obtained in low K⁺ (PDBID: 1K4D), with residues contributing to the filter shown as licorice. A key hydrogen bond between W67 and D80 is shown with yellow dashed lines.

Figure 2 |. Conformational changes in the ion selectivity filter of Kv channels

A) Side view of the structure of the Shaker Kv channel in high K⁺ (PDBID: 7SIP) with HOLE plot of the central ion permeation pathway illustrated in gray. The S5-S6 pore-forming helices from two opposing subunits are shown in green and blue, with the peripheral S1-S4 voltage-sensing domains from the other two subunits shown in pink and yellow. B) Expanded view of the ion selectivity filter with two opposing subunits of the Shaker Kv channel in a conducting conformation obtained in high K⁺ (PDBID: 7SIP), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black. A key hydrogen bond between W434 and D447 is shown with yellow dashed lines and K⁺ ions are shown as purple spheres. C) Expanded view of the ion selectivity filter with two opposing subunits of the W434F mutant Shaker channel in a C-type inactivated conformation obtained in high K⁺ (PDBID: 7SJ1), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black. Water molecules are shown as red spheres and K⁺ ions are shown as purple spheres. D) Same view as in C, but for the structure of the C-type inactivated conformation of the wild-type Shaker Kv channel in low K⁺ (PDBID: 8TEO).

Figure 3 |. Structure of the pore of P2X3 receptor channels.

A) Side view of transmembrane domain of apo P2X3 channel (PDBID: 5SVJ) with HOLE plot of the central ion permeation pathway illustrated in gray. B) Side view of P2X3 channel bound to ATP (PDBID: 5SVK) with HOLE plot of the central ion permeation pathway illustrated in gray and ATP as licorice.

Figure 4 |. Structure of the pore of TRP channels and its plasticity

A) Side view of apo TRPV1 channel structure (PDBID: 7L2H) with HOLE plot of the central ion permeation pathway illustrated in gray. The S5-S6 pore-forming helices from two opposing subunits are shown in green and blue, with the peripheral S1-S4 voltage sensor-like domains from the other two subunits shown in pink and yellow. B) Expanded view of the ion selectivity filter with two opposing subunits of the apo TRPV1 channel structure (PDBID: 7L2H), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black. A Na⁺ ion is shown as a purple sphere. C) Expanded view of the ion selectivity filter with two opposing subunits of the TRPV1 channel structure bound to activators resiniferatoxin (RTx) and double-knot toxin (DkTx) (PDBID: 7L2M), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black. Na⁺ ions are shown as purple spheres. D) Expanded view of the ion selectivity filter with two opposing subunits of the TRPV1 channel structure bound to the activator RTx and solved in the presence of NMDG⁺ (PDBID: 7L2X), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black. The NMDG⁺ ion is shown as licorice and surface representation. E) Expanded view of the ion selectivity filter with two opposing subunits of the TRPA1 channel structure bound to the inhibitor A-967079 (PDBID: 6V9Y), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black. F) Expanded view of the ion selectivity filter with two opposing subunits of the TRPA1 channel structure covalently modified by activator iodoacetamide (PDBID: 6V9X), with residues contributing to the filter shown as licorice. The HOLE plot of the central ion permeation pathway is outlined in black.