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

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.