title: 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 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), 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.
authors.affiliation: Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri - Kansas City, Kansas City, MO, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Payne
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Gerdes
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Naumchuk
authors.forename: Audrey E
authors.initials: AE
authors.lastname: McCalley
authors.forename: Simon
authors.initials: S
authors.lastname: Kaja
authors.forename: Peter
authors.initials: P
authors.lastname: Koulen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D053763:Presenilins / Q000737:chemistry / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D010455:Peptides; D053763:Presenilins; D019837:Ryanodine Receptor Calcium Release Channel; D003545:Cysteine; D002118:Calcium
keywords: Alzheimer's disease; Endoplasmic reticulum; Intracellular calcium; Neuroprotection; Oxidative stress
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