Presenilin-ryanodine receptor connection

The Presenilins (PS) gene family is composed of two members: PS1 and PS2. Mutations in PSs are linked to familial Alzheimer's disease (FAD) (1). PSs are the catalytic subunits of the γ-secretase multimolecular complex, which mediates the intramembranous cleavage of many type I membrane proteins, including amyloid precursor protein (APP) and Notch (2, 3). Cleavage of substrates produces secreted and intracellular peptides, which in many cases are involved in intracellular signaling pathways. Although the γ-secretase activity of PS is widely characterized, γ-secretase–independent activities have also been described. PS inactivation leads to impaired memory and neurodegeneration (3⇓–5), two key features of Alzheimer’s disease (AD). Although the importance of PSs in AD is well established, their precise contribution to normal brain function and to FAD pathogenesis are less clear. PSs are expressed in all tissues and cell types. Given the association of PS with FAD, much attention has been paid to the physiological and pathological role of PSs in the brain. Robust experimental evidence indicates that PSs regulate neurotransmitter release at synapses and intracellular Ca2+ homeostasis. However, how exactly this regulation takes place is not fully understood. In PNAS, a study by Wu et al. (5) provides evidence for a unique mechanism by which PSs can control both intracellular Ca2+ and transmitter release.