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Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype-specific N-terminal cysteines.


ABSTRACT: Presenilins (PS), endoplasmic reticulum (ER) transmembrane proteins, form the catalytic core of ?-secretase, an amyloid precursor protein processing enzyme. Mutations in PS lead to Alzheimer's disease (AD) by altering ?-secretase activity to generate pathologic amyloid beta and amyloid plaques in the brain. Here, we identified a novel mechanism where binding of a soluble, cytosolic N-terminal domain fragment (NTF) of PS to intracellular Ca(2+) release channels, ryanodine receptors (RyR), controls Ca(2+) release from the ER. While PS1NTF decreased total RyR-mediated Ca(2+) release, PS2NTF had no effect at physiological Ca(2+) concentrations. This differential function and isotype-specificity is due to four cysteines absent in PS1NTF, present, however, in PS2NTF. Site-directed mutagenesis targeting these cysteines converted PS1NTF to PS2NTF function and vice versa, indicating differential RyR binding. This novel mechanism of intracellular Ca(2+) regulation through the PS-RyR interaction represents a novel target for AD drug development and the treatment of other neurodegenerative disorders that critically depend on RyR and PS signaling.

SUBMITTER: Payne AJ 

PROVIDER: S-EPMC3843983 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype-specific N-terminal cysteines.

Payne Andrew J AJ   Gerdes Bryan C BC   Naumchuk Yuliya Y   McCalley Audrey E AE   Kaja Simon S   Koulen Peter P  

Experimental neurology 20130909


Presenilins (PS), endoplasmic reticulum (ER) transmembrane proteins, form the catalytic core of γ-secretase, an amyloid precursor protein processing enzyme. Mutations in PS lead to Alzheimer's disease (AD) by altering γ-secretase activity to generate pathologic amyloid beta and amyloid plaques in the brain. Here, we identified a novel mechanism where binding of a soluble, cytosolic N-terminal domain fragment (NTF) of PS to intracellular Ca(2+) release channels, ryanodine receptors (RyR), control  ...[more]

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