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Enhanced Ryanodine‐Mediated Calcium Release in Mutant PS1‐Expressing Alzheimer's Mouse Models
Author(s) -
STUTZMANN GRACE E.,
SMITH IAN,
CACCAMO ANTONELLA,
ODDO SALVATORE,
PARKER IAN,
LAFERLA FRANK
Publication year - 2007
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1379.025
Subject(s) - ryanodine receptor , calcium signaling , cytosol , microbiology and biotechnology , intracellular , inositol , calcium , chemistry , inositol trisphosphate receptor , neuroscience , receptor , signal transduction , biology , endocrinology , biochemistry , organic chemistry , enzyme
Intracellular Ca 2+ signaling involves Ca 2+ liberation through both inositol triphosphate and ryanodine receptors (IP 3 R and RyR). However, little is known of the functional interactions between these Ca 2+ sources in either neuronal physiology, or during Ca 2+ disruptions associated with Alzheimer's disease (AD). By the use of whole‐cell recordings and 2‐photon Ca 2+ imaging in cortical slices we distinguished between IP 3 R‐ and RyR‐mediated Ca 2+ components in nontransgenic (non‐Tg) and AD mouse models and demonstrate powerful signaling interactions between these channels. Ca 2+ ‐induced Ca 2+ release (CICR) through RyR contributed modestly to Ca 2+ signals evoked by photoreleased IP 3 in cortical neurons from non‐Tg mice. In contrast, the exaggerated signals in 3×Tg‐AD and PS1 KI mice resulted primarily from enhanced CICR through RyR, rather than through IP 3 R, and were associated with increased RyR expression levels. Moreover, membrane hyperpolarizations evoked by IP 3 in neurons from AD mouse models were even greater than expected simply from the exaggerated Ca 2+ signals, pointing to an increased coupling efficiency between cytosolic [Ca 2+ ] and K + channel regulation. Our results highlight the critical roles of RyR‐mediated Ca 2+ signaling in both neuronal physiology and pathophysiology, and point to presenilin ‐linked disruptions in RyR signaling as an important genetic factor in AD.