Regulation of 1, 4, 5-triphosphate receptor channel gating dynamics by mutant presenilin in Alzheimer’s disease cells

Abstract

In neurons of patients with Alzheimer’s disease, the intracellular Ca²⁺ 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 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 Ca²⁺ from IP₃Rs. As a result, the increased affinities of IP₃ and activating Ca²⁺ for IP₃R channels induce the increase in the Ca²⁺ 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.

Keywords

Ca²⁺ signal / channel / neuron / Alzheimer’s disease

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