In neurons of patients with Alzheimer＇s disease, the intracellular Ca^2＋ concentration is increased by its release from the endoplasmic reticulum via the inositol 1, 4, 5-triphosphate receptor （IP3R）. In this pape...In neurons of patients with Alzheimer＇s disease, the intracellular Ca^2＋ concentration is increased by its release from the endoplasmic reticulum via the inositol 1, 4, 5-triphosphate receptor （IP3R）. In this paper, we discuss the IP3R gating dynamics in familial Alzheimer＇s disease （FAD） cells induced with presenilin mutation PS1. By fitting the parameters of an IP3R channel model to experimental data of the open probability, the mean open time and the mean closed time of IP3R channels, in control cells and FAD mutant cells, we suggest that the interaction of presenilin mutation PS1 with IP3R channels leads the decrease in the unbinding rates of IP3 and the activating Ca^2＋ from IP3Rs. As a result, the increased affinities of IP3 and activating Ca^2＋ for IP3R channels induce the increase in the Ca^2＋ signal in FAD mutant cells. Specifically, the PS1 mutation decreases the IP3 dissociation rate of IP3R channels significantly in FAD mutant cells. Our results suggest possible novel targets for FAD therapeutic intervention.展开更多
文摘In neurons of patients with Alzheimer＇s disease, the intracellular Ca^2＋ concentration is increased by its release from the endoplasmic reticulum via the inositol 1, 4, 5-triphosphate receptor （IP3R）. In this paper, we discuss the IP3R gating dynamics in familial Alzheimer＇s disease （FAD） cells induced with presenilin mutation PS1. By fitting the parameters of an IP3R channel model to experimental data of the open probability, the mean open time and the mean closed time of IP3R channels, in control cells and FAD mutant cells, we suggest that the interaction of presenilin mutation PS1 with IP3R channels leads the decrease in the unbinding rates of IP3 and the activating Ca^2＋ from IP3Rs. As a result, the increased affinities of IP3 and activating Ca^2＋ for IP3R channels induce the increase in the Ca^2＋ signal in FAD mutant cells. Specifically, the PS1 mutation decreases the IP3 dissociation rate of IP3R channels significantly in FAD mutant cells. Our results suggest possible novel targets for FAD therapeutic intervention.
