The role of G-proteins in the regulation of pacemaking activity.

Abstract

This work is concerned with modeling the key interrelated biochemical reactions involved in initiating and inhibiting pacemaking activity in the mammalian sinoatrial node. A detailed model involving G-proteins was developed to better represent the activation pathway for adenylate cyclase. Concentration profiles of an activated G-protein complex [alpha(T)C] were established as a function of the membrane bound calcium calmodulin concentration. A previously developed model used to establish temporal profiles of cAMP was improved using the G-protein effects through the [alpha(T)C] functionality. Methods were also developed to model inhibition of G-protein by acetylcholine. Analytical solutions were developed to predict acetylcholine concentration profiles as a function of diffusion parameter and duration of acetylcholine pulses. The model was used to demonstrate suppression of cAMP by acetylcholine through G-protein pathways. It provides a basis for a tool to quantify key biochemical species during stimulation and inhibition of sinoatrial node pacemaking. A stability analysis of the model equations has potential application in studying the link between the biochemical species concentrations and abnormal effects in sinoatrial node pacemaking.