Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer’s Disease-Causing Mutants in Presenilins

Abstract

Familial Alzheimer’s disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) Ca2+ release channels resulting in enhanced IP3R channel gating in an amyloid beta (Aβ) production-independent manner. This gain-of-function enhancement of IP3R activity is considered to be the main reason behind the upregulation of intracellular Ca2+ signaling in the presence of optimal and suboptimal stimuli and spontaneous Ca2+ signals observed in cells expressing mutant PS. In this paper, we employed computational modeling of single IP3R channel activity records obtained under optimal Ca2+ and multiple IP3 concentrations to gain deeper insights into the enhancement of IP3R 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, IP3R 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 IP3R in cells expressing wild-type PS. The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca2+ concentrations and quantify the sensitivity of IP3R to its two ligands. We show that the gain-of-function enhancement is sensitive to both IP3 and Ca2+ and that very small amount of IP3 is required to stimulate IP3R channels in the presence of FAD-causing mutant PS to the same level of activity as channels in control cells stimulated by significantly higher IP3 concentrations. We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca2+ signals, which can account for the more frequent global Ca2+ signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca2+ signals in cells expressing FAD-causing mutant PS.

Mode switching of Inositol 1,4,5-trisphosphate receptor channel shapes the Spatiotemporal scales of Ca2+ signals

“…Although we do not simulate whole-cell Ca 2+ waves and oscillations, these events with large amplitude and longer duration occurring at high frequency would most likely trigger global Ca 2+ signals [31]. Consistent with the observations during single channel patch-clamp experiments [4] and recent modeling study [14], our results show that the transition of the channel behavior from gating predominantly in low mode during small events to gating in the intermediate and high modes during large events is due to the significant decrease in τ c with a slight increase in τ o of the channel (Figs. 3e and 5).…”

“…The behavior of τ o and τ c shown here is again an indication of the change in the modal behavior of the channel. This is reminiscent of experimental data where τ c of the channel was observed to drop from over a second for the low mode to less than 100 ms in intermediate and high modes [4,14]. The τ o on the other hand remained constant within a few milliseconds.…”

“…The gating of each channel is given by the 12 state model described above. We determined the state of the channel at a given time using a stochastic method described previously [12][13][14]. (r j , t) at distance r j and time t from channel j are described as: …”

“…However, in the present situation where C i changes dynamically during the evolution of blips and puffs we use the algorithm developed in [4] to characterize the modal behavior of individual channels in the cluster. A detailed description of the algorithm is given in [4] and [14] and We remark that although the single channel model shown in Fig. 1 does not include an open state when InsP 3 R gates are in the L mode, the modal characterization algorithm discussed in the previous paragraph will detect an open state in the L mode when the criterion for the L mode is met while running the algorithm on the time traces obtained for each channel during blips and puffs.…”

Emergence of ion channel modal gating from independent subunit kinetics

“…47. It was concluded that the mutation confers increased sensitivity of the channel to IP 3 , reflected in a change in occupancy of two particular aggregated states of the model (56). We cannot relate this result directly to our model, as although the model of ref.…”