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

Volodymyr Rybalchenko, Sung Yong Hwang, Nataliya Rybalchenko, Peter Koulen

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

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 NTF1-82), 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 NTF1-82 strongly increased both mean currents (EC50 = 12 nM, Hill coefficient (nH) ∼ 1) and open probability for higher sublevels for single RyR channels (EC50 = 7 nM, nH ∼ 2). Bell-shaped Ca2+-activation curve remained unchanged, suggesting that PS1 NTF1-82 allosterically potentiates RyRs, but that the channel still requires Ca2+ for activation. Corroborating such an independent mechanism, the RyR potentiation by PS1 NTF1-82 was overridden by receptor desensitization at high [Ca2+] (pCa > 5). This potentiation of RyR by PS1 NTF1-82 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.

Original languageEnglish (US)
Pages (from-to)84-97
Number of pages14
JournalInternational Journal of Biochemistry and Cell Biology
Volume40
Issue number1
DOIs
StatePublished - 2008

Keywords

  • Alzheimer's disease
  • Calcium
  • Electrophysiology
  • Ion channel
  • Protein-protein interaction

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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