Thermodynamics of voltage-gated ion channels

Abstract

Ion channels are essential for cellular signaling. Voltage-gated ion channels (VGICs) are the largest and most extensively studied superfamily of ion channels. They possess modular structural features such as voltage-sensing domains that encircle and form mechanical connections with the pore-forming domains. Such features are intimately related to their function in sensing and responding to changes in the membrane potential. In the present work, we discuss the thermodynamic mechanisms of the VGIC superfamily, including the two-state gating mechanism, sliding-rocking mechanism of the voltage sensor, subunit cooperation, lipid-infiltration mechanism of inactivation, and the relationship with their structural features.

Keywords: Gating mechanism; Inactivation; Ion channel; Membrane potential; Sliding-rocking model; Voltage sensor.

Fig. 1

Structures of tetrameric ion channels. A 2TM channel of KcsA/1K4C (Zhou et al. 2001). B Swapped 6TM channel of Kv1.2/2A79 (Long et al. 2005). C Non-swapped 6TM hyperpolarization-activated channel of HCN1/5U6O (Lee and MacKinnon 2017). From the top to bottom are the side view, top view, and topology diagrams. Structural elements from one subunit are colored as the following: VS domain, blue; S4–S5 helix, cyan; S5 (outer) helix, orange; selectivity-filter, green; S6 (inner) helix, red; and cytosolic domains, yellow. The other three subunits of the tetramer are shown in gray

Fig. 2

Dry/wet two-state model of the activation-gate. A Gibbs free energies of the dry (red, labeled as G_dry) and wet (blue, G_wet) states as functions of the radius of the activation-gate. Their crossing point corresponds to the critical radius (r_c). Increasing the hydrophobicity of the gate decreases the slope of the G_wet curve (green), resulting in a reduced critical radius. B Open probability of the gate, P_o(r) (≡[1 + exp((G_wet −G_dry)/RT)]⁻¹). Increasing the hydrophilicity of the gate shifts the P_o curve to a smaller r_c. C Schematic diagram of the gating process. In the dry state (with a yellow vapor seal), ∆Ψ_M is loaded on the activation-gate; in contrast, in the wet state (with cyan water filling), ∆Ψ_M is loaded on the selectivity-filter

Fig. 3

Sliding-rocking two-state model of the voltage-sensor domain. A Superposition of VS domains from TPC1/5DQQ (C_in state) and Na_VAb/3RVY (C_out). The C_in structure is colored in wheat color (S1, S2, and S3), orange (S4), and cyan-yellow mixed (amphipathic helices), and the C_out structure is colored in gray for clarity. Positions of one of the four conserved basic residues, R4, in the two structures are marked with blue and gray spheres, indicating a two-turn sliding movement of S4 relative to the remaining VS domain. S2 and S3 as well as the amphipathic linker helix (S2–S3) are superimposed well. B Extracellular view of the VS domains shown in panel (A). C Schematic diagram of the sliding-rocking model. In the polarization state, the VS domain has an inward-facing conformation (C_in). Upon depolarization, the outward-facing conformation (C_out) becomes energetically favored. The voltage change is sensed by positively charged residues in S4, R1–R4 marked as spheres from light to dark blue. Movements of structural elements are indicated by magenta arrows. During the conformational change, the cytosolic ends of S1–S4 are anchored to the cytosolic surface of the membrane by amphipathic helices (depicted as yellow-cyan circles)

Fig. 4

Putative mechanism of the slow inactivation of ion channels. A Kinetic model of the gating process. Represented in the box, the VS domain has a C_in state (open triangle) and a C_out state (filled triangle). On the right side, the activation-gate has a closed (C) state, open (O) state, and an inactivated (I) state. The state of the VS domain is coupled to that of the activation-gate. The thickness of the arrows indicates the rate of the corresponding reaction. B Fenestrations on the wall of the central pore in the closed state of Na_VAb/3RVY. Red electron densities correspond to lipid penetration paths. These paths are presumably enlarged upon the activation-gate is switched to the open state, thus allowing more rapid infiltration of lipid molecules into the gate pore. This panel is adapted from this figure in Payandeh et al. (2011)