Cellular modelling: experiments and simulation to develop a physiological model of G-protein control of muscarinic K+ channels in mammalian atrial cells.
The first model of G-protein-K(ACh) channel interaction was developed 14 years ago and then expanded to include both the receptor-G-protein cycle and G-protein-K(ACh) channel interaction. The G-protein-K(ACh) channel interaction used the Monod-Wyman-Changeux allosteric model with the idea that one K(ACh) channel is composed of four subunits, each of which binds one active G-protein subunit (G(betagamma)). The receptor-G-protein cycle used a previous model to account for the steady-state relationship between K(ACh) current and intracellular guanosine-5-triphosphate at various extracellular concentrations of acetylcholine (ACh). However, simulations of the activation and deactivation of K(ACh) 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 K(ACh) channel activity. They are responsible for the voltage-dependent relaxation behaviour of K(ACh) 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 K(ACh) current in the model are much faster and now fall within physiological ranges.
Murakami
Shingo
S
Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. murakami@pharma2.med.osaka-u.ac.jp
Suzuki
Shingo
S
Ishii
Masaru
M
Inanobe
Atsushi
A
Kurachi
Yoshihisa
Y
D000494:Allosteric Regulation; D000818:Animals; D003198:Computer Simulation; D004553:Electric Conductivity; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006325:Heart Atria / Q000166:cytology* / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY
D015221:Potassium Channels; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins