The N-terminus of presenilin-2 increases single channel activity of brain ryanodine receptors through direct protein-protein interaction.
Presenilin-1 (PS1) and presenilin-2 (PS2) form the catalytic core in gamma-secretase complexes and mutations in these proteins result in aberrant cleavage of amyloid precursor protein leading to accumulation of the beta-amyloid in the brain of familial Alzheimer Disease patients. PS2 possesses a hydrophilic cytoplasmic N-terminal domain (PS2 NTF1-87) dispensable for gamma-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 Ca(2+) 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.
Hayrapetyan
Volodya
V
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107-2699, USA.
Rybalchenko
Volodymyr
V
Rybalchenko
Nataliya
N
Koulen
Peter
P
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D053766:Presenilin-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D053766:Presenilin-2; D011993:Recombinant Fusion Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium