Analyzing and Quantifying the Gain-of-Function Enhancement of IP(3) Receptor Gating by Familial Alzheimer’s Disease-Causing Mutants in Presenilins

Familial Alzheimer’s disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) Ca(2+) release channels resulting in enhanced IP(3)R channel gating in an amyloid beta (Aβ) production-independent manner. This gain-of-function enhancement of IP(3)R activity is considered to be the main reason behind the upregulation of intracellular Ca(2+) signaling in the presence of optimal and suboptimal stimuli and spontaneous Ca(2+) signals observed in cells expressing mutant PS. In this paper, we employed computational modeling of single IP(3)R channel activity records obtained under optimal Ca(2+) and multiple IP(3) concentrations to gain deeper insights into the enhancement of IP(3)R function. We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP(3)R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP(3)R in cells expressing wild-type PS. The model is then used to extrapolate the behavior of the channel to a wide range of IP(3) and Ca(2+) concentrations and quantify the sensitivity of IP(3)R to its two ligands. We show that the gain-of-function enhancement is sensitive to both IP(3) and Ca(2+) and that very small amount of IP(3) is required to stimulate IP(3)R channels in the presence of FAD-causing mutant PS to the same level of activity as channels in control cells stimulated by significantly higher IP(3) concentrations. We further demonstrate with simulations that the relatively longer time spent by IP(3)R in the H mode leads to the observed higher frequency of local Ca(2+) signals, which can account for the more frequent global Ca(2+) signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca(2+) signals in cells expressing FAD-causing mutant PS.