Voltage-Gated K+ Channels
Potassium Channels
K+ channels are membrane proteins that allow rapid and selective flow of K+ ions across the cell membrane, and thus generate electrical signals in cells. Voltage-gated K+ channels (Kv channels), present in all animal cells, open and close upon changes in the transmembrane potential. Kv channels are one of the key components in generation and propagation of electrical impulses in nervous system. Upon changes in transmembrane potential, these channels open and allow passive flow of K+ ions from the cell to restore the membrane potential.
Voltage Gating
Schematic view of the gating process in Kv channels.
The tetrameric structure of Kv channels is made of two functionally and structurally independent domains: an ion conduction pore, and voltage-sensor domains. The ion conduction pore is made of four subunits which are arranged symmetrically around the conduction pathway. Voltage-sensor domains are positioned at the periphery of the channel and consist of four transmembrane segments (S1-S4). Structural rearrangement of the voltage-sensor domains in response to changes in the membrane potential, and in particular S4, which includes positively charged amino acids at every third position, results in conformational changes in the conduction pore, which could open or occlude the ion conduction pathway. The nature of these movements and conformational changes in the voltage-sensors have been subject to controversy and several models for voltage-gating have been proposed.
The recently solved crystal structure of Kv1.2, from rat brain, revealed the molecular architecture of the voltage sensor domain in an open state of the channel. Four Arginine gating residues are identified in the voltage-sensor domain shielded from the lipid molecules. Coupling of the voltage-sensors to the (gate in the) pore domain is via an amphipathic alpha helix that runs parallel to the membrane plane inside the cell. Conformational changes in the voltage-sensor domain are transferred to the ion conduciton pore via the helical linker, and result in opening or closing of the intracellular gate of the ion conduction pathway. However, the nature of this coupling, and the interactions between the linker and the pore still remains a mystery.
Ion Permeation
The structural element responsible for the high selectivity of the channel, is a sequence of five amino acids that is highly conserved among potassium channels, voltage-gated or not. This stretch of amino acids, TVGYG, forms the narrowest part of the channel, also known as the selectivity filter. The ion conduction pathway is lined with oxygen atoms in this region which provide four binding sites for K+ ions. The ion conduction mechanism through the selectivity filter, has been postulated and studied . Our recent molecular dynamics study of the pore domain of Kv1.2, could provide trajectories of K+ ion conduction through the channel driven by a voltage bias across the lipid bilayer (click here to download a movie of the conduction trajectory (mpeg, 1.6M)). Our results are consistent with the knock-on mechanism suggested by Hodgkin and Keynes, in 1955. During the simulation the selectivity filter is occupied by 2 or 3 K+ ions at each time. The ions reside mainly at sites identified previously by crystallography and modeling, separated by water molecules. When a K+ ion approaches the filter from the cytoplasmic side, the configuration of the ions inside the selectivity filter changes, until the K+ ion enters the selectivity filter. Upon entrance of the K+ ion to the selectivity filter from the cytoplasmic side, the outermost K+ exits the channel to the extracellular solution. The jumps of ions between these sites and the sequence of multi-ion configurations involved in permeation are described thoroughly in here.
Different scenarios for the K+ conduction through the selectivity filter were observed in our simulations, for which movies of the simulation trajectories are provided here (mpeg, 4.7M) and here (mpeg, 1.4M).
Publications
Dynamics of K+ ion conduction through Kv1.2. Fatemeh Khalili-Araghi, Emad Tajkhorshid, and Klaus Schulten. Biophysical Journal, 91:L72-L74, 2006.
Investigators
Page created and maintained by Fatemeh Khalili-Araghi.