The N-terminus of presenilin-2 increases single channel activity of brain ryanodine receptors through direct protein-protein interaction

Volodya Hayrapetyan, Volodymyr Rybalchenko, Nataliya Rybalchenko, Peter Koulen

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Presenilin-1 (PS1) and presenilin-2 (PS2) form the catalytic core in γ-secretase complexes and mutations in these proteins result in aberrant cleavage of amyloid precursor protein leading to accumulation of the β-amyloid in the brain of familial Alzheimer Disease patients. PS2 possesses a hydrophilic cytoplasmic N-terminal domain (PS2 NTF1-87) dispensable for γ-secretase activity with physiological functions yet to be determined. The effects of this soluble 87 amino acid fragment of mouse PS2 on single channel activity of mouse brain ryanodine receptors (RyR) were determined. PS2 NTF1-87 application to the cytoplasmic side of the RyR significantly increased single channel activity by favoring higher sublevel openings. The Ca2+ activation and desensitization ranges for RyRs were unchanged. We demonstrate facilitation of RyR gating by PS2 NTF1-87, which might represent a general mechanism of RyR regulation by presenilins potentially prone to be affected by mutations or external stimuli contributing to the development of neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)507-518
Number of pages12
JournalCell Calcium
Volume44
Issue number5
DOIs
StatePublished - Nov 2008

Fingerprint

Presenilin-2
Ryanodine Receptor Calcium Release Channel
Brain
Amyloid Precursor Protein Secretases
Proteins
Presenilins
Presenilin-1
Mutation
Amyloid beta-Protein Precursor
Amyloid
Neurodegenerative Diseases
Catalytic Domain
Alzheimer Disease
Amino Acids

Keywords

  • Alzheimer's disease
  • Calcium
  • FAD
  • Familial AD
  • FTD
  • Gamma secretase
  • Ion channel gating
  • Mouse
  • Neurodegenerative disease
  • Presenilin-1
  • Sporadic AD

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

The N-terminus of presenilin-2 increases single channel activity of brain ryanodine receptors through direct protein-protein interaction. / Hayrapetyan, Volodya; Rybalchenko, Volodymyr; Rybalchenko, Nataliya; Koulen, Peter.

In: Cell Calcium, Vol. 44, No. 5, 11.2008, p. 507-518.

Research output: Contribution to journalArticle

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