Gain-of-Function Enhancement of IP ₃ Receptor Modal Gating by Familial Alzheimer’s Disease–Linked Presenilin Mutants in Human Cells and Mouse Neurons

Abstract

Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1, PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca 2+ ) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. Here, we demonstrate that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (InsP 3 R) Ca 2+ release channel by a gain-offunction effect that mirrors the genetics of FAD and is independent of secretase activity. In contrast, wild type PS or PS mutants that cause frontotemporal dementia have no such effect. FAD PS alter InsP 3 R channel gating by modal switching. Recordings of endogenous InsP 3 R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed they have higher occupancy in a high open probability burst mode compared to that of InsP 3 R in cells with wild-type PS, resulting in enhanced Ca 2+ signaling. These results indicate that exaggerated Ca 2+ signaling through InsP 3 R-PS interaction is a disease-specific and robust proximal mechanism in FAD.

Emergence of ion channel modal gating from independent subunit kinetics

“…This result is associated with a shorter mean closed time and an equivalent mean open time (Fig. 7), as seen experimentally (12).…”

“…Furthermore, experimental traces in ref. 12 show that channels exhibiting high P O still exhibit long channel closures of several seconds. In the context of the model, this means that the slow sequestering transition must still be intact.…”

“…The reasoning here depends only weakly on the parameters of the model and therefore encompasses the wide variety of cell types studied by ref. 12, regardless of differences in finer kinetic detail. Our model provides a useful tool to pursue this issue in concert with molecular studies and to explore further questions such as the potential connection to IP 3 sensitization by PKA (53) and cAMP (57).…”

“…The enhancement of IP 3 R activity by mutant presenilins is a key contributor to the pathogenesis of familial Alzheimer's disease. This is attributed to an increase in the prevalence of H mode, at the expense of L mode (12), leading to a disruption of Ca 2+ homeostasis. This was recently examined using the whole-channel model of ref.…”

“…Recently, it has been revealed that the main method of ligand regulation is to affect a slow switching between distinct levels of channel activity-a phenomenon known as modal gating (7)(8)(9). IP 3 R modal gating has pronounced implications for the dynamics of Ca 2+ release events (10), and its dysfunction has been implicated in the pathogenesis of familial Alzheimer's disease (11,12). A detailed understanding of this important feature of IP 3 R behavior is therefore crucial for unraveling the complexity of Ca 2+ signaling and its role in cell function and disease.…”