Na+ and K+ channels: history and structure

Abstract

In this perspective, we discuss the physiological roles of Na and K channels, emphasizing the importance of the K channel for cellular homeostasis in animal cells and of Na and K channels for cellular signaling. We consider the structural basis of Na and K channel gating in light of recent structural and electrophysiological findings.

Figure 1

Structure of a voltage-gated K channel. Shown are the structures of the chimeric Kv1.2/2.1 channel (8). (A) An extracellular view with the four subunits shown as wireframe and the S1–S6 transmembrane helices of one subunit shown as ribbons. The pore is formed by the S5 (black) and S6 (cyan) helices; pore lining residues from the S6 helices are in spacefill (gray). The voltage sensors, formed by helices S1–S4, are found next to the pore forming helices of an adjacent subunit. The S4–5 helix (dark blue) transmits downward movement of the S4 helix (blue) to the S6. (B) Shown is a side view after a 90° rotation of (A). (C) An enlarged side view of the pore is shown with the pore lining residues from two subunits in spacefill (gray). Three K ions (gold) are shown, two in the selectivity filter (black strands), that are coordinated by the backbone carbonyl oxygens of the selectivity filter residues (not shown). The third K ion is in the vestibule, or cavity, surrounded by eight waters of hydration (gray/pink). This hydrated K⁺ ion is at the position of the hydrated K⁺ ion in the KcsA structure (5). (D) Hydrophobic residues on the S4, S4–5, and S6 helices and on the S5 helix (S5_a) of the subunit adjacent to the voltage sensor are shown in spacefill (gray). Polar residues at the intracellular end of S6 are also in spacefill (color CPK). To see this figure in color, go online.

Figure 2

Detailed view of the voltage-sensing mechanism. Helices from Fig. 1 are shown with selected residues in spacefill. (A) The open state structure from (8) is shown. The S4 helices are in an activated position, and the intracellular gate is open. Selected residues are shown in spacefill with CPK coloring. Residue numbering is for the chimeric structure, and add 72 to obtain corresponding residues in the Shaker sequence. Negatively charged residues QTC_O and QTC_i are E226 and E236 on the S2 helix. Not shown are F233 on S2 and D259 on S3, which also contribute to the QTC (9). R2–R6 are positively charged residues on S4. K7 is at the start of the S4–5 helix from which three leucine residues (gray, L310, L313, and L317) point into the membrane. Amino acid S320, at the end of the S4–5 helix, is hydrogen bonded to N408 on the S6 helix (inset). The two proline residues (P401 and P403, pink) are likely hinge points on the S6 helix. Two hydrophilic residues R415 and E416 at the intracellular end of the S6 are shown. K7 and E416 likely interact in the open and closed states. (B) A hypothetical closed state of the chimeric structure of Long et al. (8) is shown. The S4 moves downward and the S4–5 and distal S6 rotate so that the distal S6 helix approximates the position of the pore-lining M2 helix of KcsA (4,5). The S4–5 is rotated around S320 and the distal S6 around P401. To see this figure in color, go online.

Figure 3

Position of S4 helices and functional states of the Na channel. Upper: possible positions of the S4 helices of the four domains of the Na channel in different functional states are shown relative to the QTC. Lower: highly simplified cartoons show the intracellular gate and inactivation particle in the different states. The black circle represents a Na ion and the gray circle waters of hydration.