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

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Authors: Payne, A. J.; Gerdes, B. C.; Naumchuk, Y.; McCalley, A. E.; Kaja, S.; Koulen, P.
Article 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 gamma-secretase, an amyloid precursor protein processing enzyme. Mutations in PS lead to Alzheimer's disease (AD) by altering gamma-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.
Journal Title: Experimental neurology
Volume: 250
ISSN: 1090-2430; 0014-4886
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: 143
End Page: 150
Language: ENG
DOI/URL:

10.1016/j.expneurol.2013.09.001
Notes: LR: 20161019; CI: (c) 2013; GR: P01 AG022550/AG/NIA NIH HHS/United States; GR: P01 AG027956/AG/NIA NIH HHS/United States; GR: AG010485/AG/NIA NIH HHS/United States; GR: R01 EY014227/EY/NEI NIH HHS/United States; GR: AG022550/AG/NIA NIH HHS/United States; GR: P01 AG010485/AG/NIA NIH HHS/United States; GR: EY014227/EY/NEI NIH HHS/United States; GR: R01 EY022774/EY/NEI NIH HHS/United States; GR: EY022774/EY/NEI NIH HHS/United States; GR: RR022570/RR/NCRR NIH HHS/United States; GR: AG027956/AG/NIA NIH HHS/United States; GR: S10 RR027093/RR/NCRR NIH HHS/United States; GR: S10 RR022570/RR/NCRR NIH HHS/United States; GR: RR027093/RR/NCRR NIH HHS/United States; JID: 0370712; 0 (Peptides); 0 (Presenilins); 0 (Ryanodine Receptor Calcium Release Channel); K848JZ4886 (Cysteine); SY7Q814VUP (Calcium); NIHMS523965; OID: NLM: NIHMS523965; OID: NLM: PMC3843983; OTO: NOTNLM; 2013/06/25 [received]; 2013/08/23 [revised]; 2013/09/01 [accepted]; ppublish