The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity.
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)=12nM, Hill coefficient (n(H)) approximately 1) and open probability for higher sublevels for single RyR channels (EC(50)=7nM, n(H) approximately 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 PS1 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.
Rybalchenko
Volodymyr
V
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
Hwang
Sung-Yong
SY
Rybalchenko
Nataliya
N
Koulen
Peter
P
D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D003600:Cytosol / Q000502:physiology; D015640:Ion Channel Gating; D051379:Mice; D008861:Microsomes / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D053764:Presenilin-1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
D010446:Peptide Fragments; D053764:Presenilin-1; D011994:Recombinant Proteins; D019837:Ryanodine Receptor Calcium Release Channel