Mechanism of Electromechanical Coupling in Voltage-Gated Potassium Channels

Abstract

Voltage-gated ion channels play a central role in the generation of action potentials in the nervous system. They are selective for one type of ion – sodium, calcium, or potassium. Voltage-gated ion channels are composed of a central pore that allows ions to pass through the membrane and four peripheral voltage sensing domains that respond to changes in the membrane potential. Upon depolarization, voltage sensors in voltage-gated potassium channels (Kv) undergo conformational changes driven by positive charges in the S4 segment and aided by pairwise electrostatic interactions with the surrounding voltage sensor. Structure-function relations of Kv channels have been investigated in detail, and the resulting models on the movement of the voltage sensors now converge to a consensus; the S4 segment undergoes a combined movement of rotation, tilt, and vertical displacement in order to bring 3–4e+ each through the electric field focused in this region. Nevertheless, the mechanism by which the voltage sensor movement leads to pore opening, the electromechanical coupling, is still not fully understood. Thus, recently, electromechanical coupling in different Kv channels has been investigated with a multitude of techniques including electrophysiology, 3D crystal structures, fluorescence spectroscopy, and molecular dynamics simulations. Evidently, the S4–S5 linker, the covalent link between the voltage sensor and pore, plays a crucial role. The linker transfers the energy from the voltage sensor movement to the pore domain via an interaction with the S6 C-termini, which are pulled open during gating. In addition, other contact regions have been proposed. This review aims to provide (i) an in-depth comparison of the molecular mechanisms of electromechanical coupling in different Kv channels; (ii) insight as to how the voltage sensor and pore domain influence one another; and (iii) theoretical predictions on the movement of the cytosolic face of the Kv channels during gating.

Cooperative Activation of the T-type CaV3.2 Channel

“…The Q/Q max curve was shifted to the same extent and overlapped with the G/G max curve as it was also shown for the WT channel. This tight coupling between the conductance and the charge means that electromechanical coupling was not altered, and suggests that V907G stabilized the pore in its open state (65). Remarkably, introduction of glycine residues at positions 902, 903, 904, 906, 908, 909, 911, 912, and 913 did not significantly alter ⌬G act (p Ͼ 0.01).…”

“…sufficient to disrupt the interaction and the pore would then open passively in the absence of any physical hindrance (65). It is also possible that the S4-S5 linker and the pore S6 residues remain in close contact during activation and are being pulled away simultaneously as a single unit.…”

Dynamics of internal pore opening in K V channels probed by a fluorescent unnatural amino acid

“…It is thought that the four voltage sensors activate independently, and only after all four have activated, the central pore opens cooperatively (8,9). This mechanism implies that the energy generated by the movement of the first three voltage sensors has to be "conserved" in the system and has to be released to the pore during opening (10). The linear interpolations between closed and open structures leave the basis of both cooperativity and energy conservation unknown.…”

Do Lipids Show State-dependent Affinity to the Voltage-gated Potassium Channel KvAP?

“…This movement is energetically coupled to the pore helices (S5-S6) and triggers pore opening (reviewed in Ref. 3).…”