The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity

Ryanodine receptors (RyRs) amplify intracellular Ca²⁺ signals by massively releasing Ca²⁺ from intracellular stores. Exaggerated chronic Ca²⁺ release can trigger cellular apoptosis underlying a variety of neurodegenerative diseases. Aberrant functioning of presenilin-1 (PS1) protein instigates Ca²⁺-dependent apoptosis, providing a basis for the "calcium hypothesis" of Alzheimer's disease (AD). To get insight into this problem, we hypothesized that the previously reported physical interaction between RyR and PS1 modulates functional properties of the RyR. We generated a soluble cytoplasmic N-terminal fragment of PS1 comprising the first 82 amino acid (PS1 NTF_1-82), the candidate for interaction with putative cytoplasmic modulatory sites of the RyR, and studied its effect on single channel currents of mouse brain RyRs incorporated in lipid bilayers. PS1 NTF_1-82 strongly increased both mean currents (EC₅₀ = 12 nM, Hill coefficient (n_H) ∼ 1) and open probability for higher sublevels for single RyR channels (EC₅₀ = 7 nM, n_H ∼ 2). Bell-shaped Ca²⁺-activation curve remained unchanged, suggesting that PS1 NTF_1-82 allosterically potentiates RyRs, but that the channel still requires Ca²⁺ for activation. Corroborating such an independent mechanism, the RyR potentiation by PS1 NTF_1-82 was overridden by receptor desensitization at high [Ca²⁺] (pCa > 5). This potentiation of RyR by PS1 NTF_1-82 reveals a new mechanism of physiologically relevant PS1-regulated Ca²⁺ release from intracellular stores, which could be alternative or additional to recently reported intracellular Ca²⁺ leak channels formed by PS1 holoproteins.