Contribution of the kinetics of G protein dissociation to the characteristic modifications of N-type calcium channel activity

TL;DR

This study models how G protein dissociation kinetics influence the characteristic biophysical modifications of N-type calcium channel activity, highlighting the importance of dissociation parameters in channel regulation.

Contribution

It introduces a simple kinetic scheme to describe G protein effects on calcium channels, emphasizing the role of dissociation kinetics and auxiliary subunits in channel regulation.

Findings

G protein dissociation kinetics significantly affect channel behavior.

A simple three-parameter model can describe most channel modifications.

Auxiliary beta subunits modulate G protein regulation effects.

Abstract

Direct G protein inhibition of N-type calcium channels is recognized by characteristic biophysical modifications. In this study, we quantify and simulate the importance of G protein dissociation on the phenotype of G protein-regulated whole-cell currents. Based on the observation that the voltage-dependence of the time constant of recovery from G protein inhibition is correlated with the voltage-dependence of channel opening, we depict all G protein effects by a simple kinetic scheme. All landmark modifications in calcium currents, except inhibition, can be successfully described using three simple biophysical parameters (extent of block, extent of recovery, and time constant of recovery). Modifications of these parameters by auxiliary beta subunits are at the origin of differences in N-type channel regulation by G proteins. The simulation data illustrate that channel reluctance can occur as the result of an experimental bias linked to the variable extent of G protein dissociation when peak currents are measured at various membrane potentials. To produce alterations in channel kinetics, the two most important parameters are the extents of initial block and recovery. These data emphasize the contribution of the degree and kinetics of G protein dissociation in the modification of N-type currents.