Mechanism of electromechanical coupling in voltage-gated potassium channels.

Rikard Blunck,Zarah Batulan

doi:10.3389/fphar.2012.00166

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.

Highlights

Voltage-gated potassium channels (Kv) are a group of membrane proteins that regulate the flow of potassium ions into and out of cells in response to changes in the membrane potential
Kv channels assemble as symmetric tetramers, with each subunit consisting of six transmembrane α-helices (S1–S6) connected by five linker regions
The findings indicated that, similar to Kv channels, electromechanical coupling in Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is mediated from the S4–S5 linker to the S6T

Summary

Introduction

Voltage-gated potassium channels (Kv) are a group of membrane proteins that regulate the flow of potassium ions into and out of cells in response to changes in the membrane potential. Kv channels are found throughout the body in different cell types Their expression in neuronal and muscle tissues helps generate action potentials as well as maintain the resting membrane potential, thereby playing a critical role in cellular excitability in the central nervous and cardiac systems. Other roles of this class of proteins include regulation of hormone release such as the insulin secretion pathway (MacDonald and Wheeler, 2003) and implication in immune response (Koo et al, 1997; Beeton et al, 2001; Blunck et al, 2001; Thomas et al, 2011). The S5–S6 linker forms a re-entrant loop (p-loop), arranging at the extracellular funnel into a small pore helix and the selectivity filter responsible for the preference for potassium over sodium in K+ channels (Doyle et al, 1998)

Objectives

Conclusion