Shaker potassium channel gating. III: Evaluation of kinetic models for activation.

Abstract

AaSTgACT Predictions of different classes of gating models involving identical conformational changes in each of four subunits were compared to the gating behavior of Shaker potassium channels without N-type inactivation. Each model was tested to see if it could simulate the voltage dependence of the steady state open probability, and the kinetics of the single-channel currents, macroscopic ionic currents and macroscopic gating currents using a single set of parameters. Activation schemes based upon four identical single-step activation processes were found to be incompatible with the experimental results, as were those involving a concerted, opening transition. A model where the opening of the channel requires two conformational changes in each of the four subunits can adequately account for the steady state and kinetic behavior of the channel. In this model, the gating in each subunit is independent except for a stabilization of the open state when all four subunits are activated, and an unstable closed conformation that the channel enters after opening. A small amount of negative cooperativity between the subunits must be added to account quantitatively for the dependence of the activation time course on holding voltage.

From Structure to Function in Open Ionic Channels

“…Nonetheless, one must wonder what prefactor is actually used in theories of activation that apply at a range membrane potentials (Schoppa & Sigworth, 1998;Zagotta, Hoshi & Aldrich, 1994). One must wonder whether the distressingly large number of states in those models reflects the complexities of the gating process or the inadequacy of the models and basis functions (exponentials) being used to describe it.…”

A Geometric Comparison of Single Chain Multi-State Models of Ion Channel Gating

“…As has been observed by others, for example Zagotta et al (1994a), tail currents for some channels display a nearly single exponential time course of deactivation. This suggests an HH type chain in the activation pathway, however, models of specific ion channels often involve inactivation or passage from the open state to states not directly in the activation pathway (Zagotta et al, 1994b;Bezanilla, 2000). These additional states have the potential of significantly altering the kinetics of the open state.…”

“…For example, a multi-state model that is equivalent to the classical Hodgkin-Huxley model for the sodium conductance in the squid giant axon is where x 4 is the open state and the m and h subscripts refer to the activation and inactivation rate functions. Other models including inactivation tend to have less symmetry than the above model but also introduce loop connections between a number of states (Bezanilla, 2000;Zagotta et al, 1994b). More work needs to be done on such models to get a fundamental understanding of their behaviour.…”

“…The rate functions are simple exponentials (the most most commonly employed functional form for voltage-dependent rates (Zagotta et al, 1994b;Chanda and Bezanilla, 2002;Kargol et al, 2002;Piper et al, 2003)) of the form…”

“…Typically, the states are ordered in a partial sequence with each state connected to usually two, sometimes three, or at most four others. The rate functions are often restricted by dictating that all or a set of the forward rates be identical or integer multiples of each other, and the reverse rates similarly (Zagotta et al, 1994b;Roux et al, 1998;Bezanilla, 2000;Bähring et al, 2001;Chanda and Bezanilla, 2002;Piper et al, 2003). Aggregation of similarly behaving states can also be performed to yield some simplification (Kienker, 1989;Kijima and Kijima, 1997).…”