Gating of voltage-dependent potassium channels

Abstract

Activation of voltage-dependent ion channels is primarily controlled by the applied potential difference across the membrane. For potassium channels the Drosophila Shaker channel has served as an archetype of all other potassium channels in studies of activation mechanisms. In the Shaker potassium channel much of the voltage sensitivity is conferred by the S4 transmembrane helix, which contains seven positively charged residues. During gating, the movement of these charges produces gating currents. Mutagenic and fluorescence studies indicate that four of these residues are particularly important and contribute to the majority of gating charge, R362, R365, R368 and R371. The channel is thought to dwell in several closed states prior to opening. Ionic-charge pairing with negatively charged residues in the S2 and S3 helices is thought to be important in regulating these closed states and detailed kinetic models have attempted to define the kinetics and charge of the transitions between these states. Neutral residues throughout the S4 and S5 helices are thought to control late steps in channel opening and may have important roles in modulating the stability of the open state and late closed states. In response to depolarization, the S4 helix is thought to undergo a rotational translation and this movement is also important in studies of the movement of the pore helices, S5 and S6, during opening. This review will examine residues that are important during activation as well as kinetic models that have attempted to quantitatively define the activation pathway of voltage-dependent potassium channels.

Functional Equilibrium of the KcsA Structure Revealed by NMR

“…Methyl-TROSY spectra were acquired as reported previously (15). 13 C ZZ exchange spectra were acquired and analyzed as described previously (21). The signal intensities of the four peaks from V76 ␥(B) (namely, the auto peak of the permeable conformation, I pp ; that of the impermeable conformation, I ii ; the cross peak from the permeable to the impermeable conformations, I pi ; and that from the impermeable to the permeable conformations, I ip ) were acquired with eight or nine mixing times, T. All data points were simultaneously fitted to the theoretical equation…”

“…Eventually, the current reaches a plateau where the current is only 10 -15% of the peak current. This process, called activation-coupled inactivation, is also observed in C-type inactivation for many K v channels upon depolarization of the membrane (13). On the basis of the structural similarity of the pore domains, the inactivation of KcsA is assumed to be caused by a similar mechanism to that of the C-type inactivation of K v channels.…”

Structural basis underlying the dual gate properties of KcsA

“…The activation and subsequent inactivation are referred to as activation-coupled inactivation, which is also observed for the eukaryotic voltage-dependent K (Kv) channels (2)(3)(4). In vertebrates, the inactivation of Kv channels is important for determining the action potential duration and the shape and characteristics of any action potential plateau (5). Therefore, KcsA would serve as a good prototype of Kv channels, and a structural analysis of KcsA could clarify the mechanism of the Kv channel function, including the activation-coupled C-type inactivation.…”

Ion channel gating: A first-passage time analysis of the Kramers type

“…Nevertheless, such an approach presents a fitting procedure; as such it is intimately connected with the danger of a proliferation of parameters. In particular, kinetic schemes containing as many as 14 structurally unidentified closed substates have been proposed (21).…”