期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 40, 期 1, 页码 84-97出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2007.06.023
关键词
Alzheimer's disease; protein-protein interaction; calcium; ion channel; electrophysiology
资金
- NATIONAL EYE INSTITUTE [R01EY014227] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG022550] Funding Source: NIH RePORTER
- NEI NIH HHS [EY14227, R01 EY014227] Funding Source: Medline
- NIA NIH HHS [P01 AG022550, AG022550] Funding Source: Medline
Ryanodine receptors (RyRs) amplify intracellular Ca(2+) signals by massively releasing Ca(2+) from intracellular stores. Exaggerated chronic Ca(2+) release can trigger cellular apoptosis underlying a variety of neurodegenerative diseases. Aberrant functioning of presenilin-1 (PS1) protein instigates Ca(2+)-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 NTF(1-82)), 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 NTF(1-82) strongly increased both mean currents (EC(50) = 12 nM, Hill coefficient (nH) similar to 1) and open probability for higher sublevels for single RyR channels (EC50 = 7 nM, nH similar to 2). Bell-shaped Ca(2+)-activation curve remained unchanged, suggesting that PS1 NTF(1-82) allosterically potentiates RyRs, but that the channel still requires Ca(2+) for activation. Corroborating such an independent mechanism, the RyR potentiation by PS I NTF(1-82) was overridden by receptor desensitization at high [Ca(2+)] (pCa>5). This potentiation of RyR by PS1 NTF(1-82) reveals a new mechanism of physiologically relevant PS1-regulated Ca(2+) release from intracellular stores, which could be alternative or additional to recently reported intracellular Ca(2+) leak channels formed by PS1 holoproteins. (C) 2007 Elsevier Ltd. All rights reserved.
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