Voltage dependence of Hodgkin-Huxley rate functions for a multi-stage K channel voltage sensor within a membrane

TL;DR

This paper models the voltage dependence of Hodgkin-Huxley rate functions for multi-stage potassium channels using a Brownian particle framework, deriving conditions under which voltage-dependent behaviors and oscillations occur.

Contribution

It introduces a stochastic energy landscape model for multi-stage K+ channel activation, deriving voltage-dependent rate functions and oscillation conditions.

Findings

Derived voltage-dependent rate functions for multi-stage K+ channels.

Identified conditions for small amplitude oscillations and mixed-mode oscillations.

Showed similarity of derived rate functions to classical Hodgkin-Huxley functions.

Abstract

The activation of a $K^+$ channel sensor in two sequential stages during a voltage clamp may be described as the translocation of a Brownian particle in an energy landscape with two large barriers between states. A solution of the Smoluchowski equation for a square-well approximation to the potential function of the S4 voltage sensor satisfies a master equation, and has two frequencies that may be determined from the forward and backward rate functions. When the higher frequency terms have small amplitude, the solution reduces to the relaxation of a rate equation, where the derived two-state rate functions are dependent on the relative magnitude of the forward rates ($\alpha$ and $\gamma$) and the backward rates ($\beta$ and $\delta$) for each stage. In particular, the voltage dependence of the Hodgkin-Huxley rate functions for a $K^+$ channel may be derived by assuming that the rate functions of the first stage are large relative to those of the second stage - $\alpha \gg \gamma $ and $\beta \gg \delta$. For a {\em Shaker} IR $K^+$ channel, the first forward and backward transitions are rate limiting ($\alpha < \gamma $ and $\delta \ll \beta$), and for an activation process with either two or three stages, the derived two-state rate functions also have a voltage dependence that is of a similar form to that determined for the squid axon. The potential variation generated by the interaction between a two-stage $K^+$ ion channel and a noninactivating $Na^+$ ion channel is determined by the master equation for $K^+$ ion channel activation and the ionic current equation when the $Na^+$ ion channel activation time is small, and if $\beta \ll \delta $ and $\alpha \ll \gamma $, the system may exhibit a small amplitude oscillation between spikes, or mixed-mode oscillation.