Cellular modelling: Experiments and simulation to develop a physiological model of G-protein control of muscarinic K+ channels in mammalian atrial cells

Abstract

The first model of G-protein-KAch channel interaction was developed 14 years ago and then expanded to include both the receptor-G-protein cycle and G-protein-KAch channel interaction. The G-protein-K Ach channel interaction used the Monod-Wyman-Changeux allosteric model with the idea that one KAch channel is composed of four subunits, each of which binds one active G-protein subunit (G). The receptor-G-protein cycle used a previous model to account for the steady-state relationship between KAch current and intracellular guanosine-5-triphosphate at various extracellular concentrations of acetylcholine (ACh). However, simulations of the activation and deactivation of KAch current upon ACh application or removal were much slower than experimental results. This clearly indicates some essential elements were absent from the model. We recently found that regulators of G-protein signalling are involved in the control of KAch channel activity. They are responsible for the voltage-dependent relaxation behaviour of KAch channels. Based on this finding, we have improved the receptor-G-protein cycle model to reproduce the relaxation behaviour. With this modification, the activation and deactivation of KAch current in the model are much faster and now fall within physiological ranges. This journal is ? 2010 The Royal Society.