Peripheral Site Acetylcholinesterase Blockade Induces RACK1-Associated Neuronal Remodeling (original) (raw)
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Research Articles| June 29 2007
aDepartments of Neurobiology and
bBiological Chemistry, Institute of Life Sciences and
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bBiological Chemistry, Institute of Life Sciences and
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bBiological Chemistry, Institute of Life Sciences and
dThe Wolfson Center for Applied Structural Biology, The Hebrew University of Jerusalem, Jerusalem, Israel; Departments of
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eAnesthesia and
fPhysiology, University of Toronto, Toronto, Ont., Canada
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eAnesthesia and
fPhysiology, University of Toronto, Toronto, Ont., Canada
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bBiological Chemistry, Institute of Life Sciences and
Search for other works by this author on:
bBiological Chemistry, Institute of Life Sciences and
dThe Wolfson Center for Applied Structural Biology, The Hebrew University of Jerusalem, Jerusalem, Israel; Departments of
Search for other works by this author on:
eAnesthesia and
fPhysiology, University of Toronto, Toronto, Ont., Canada
Search for other works by this author on:
aDepartments of Neurobiology and
cThe Israel Interdisciplinary Center for Neuronal Computation, The Hebrew University of Jerusalem,
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eAnesthesia and
fPhysiology, University of Toronto, Toronto, Ont., Canada
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bBiological Chemistry, Institute of Life Sciences and
cThe Israel Interdisciplinary Center for Neuronal Computation, The Hebrew University of Jerusalem,
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Neurodegener Dis (2007) 4 (2-3): 171–184.
Citation
Noa Farchi, Keren Ofek, Erez Podoly, Haiheng Dong, Yun-Yan Xiang, Sophia Diamant, Oded Livnah, Jingxin Li, Binyamin Hochner, Wei-Yang Lu, Hermona Soreq; Peripheral Site Acetylcholinesterase Blockade Induces RACK1-Associated Neuronal Remodeling. _Neurodegener Dis 1 June 2007; 4 (2-3): 171–184. https://doi.org/10.1159/000101842
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Abstract
Background: Peripheral anionic site (PAS) blockade of acetylcholinesterase (AChE) notably affects neuronal activity and cyto-architecture, however, the mechanism(s) involved are incompletely understood. Objective: We wished to specify the PAS extracellular effects on specific AChE mRNA splice variants, delineate the consequent cellular remodeling events, and explore the inhibitory effects on interchanging RACK1 interactions. Methods: We exposed rat hippocampal cultured neurons to BW284C51, the peripheral anionic site inhibitor of AChE, and to the non-selective AChE active site inhibitor, physostigmine for studying the neuronal remodeling of AChE mRNA expression and trafficking. Results: BW284C51 induced overexpression of both AChE splice variants, yet promoted neuritic translocation of the normally rare AChE-R, and retraction of AChE-S mRNA in an antisense-suppressible manner. BW284C51 further caused modest decreases in the expression of the scaffold protein RACK1 (receptor for activated protein kinase βII), followed by drastic neurite retraction of both RACK1 and the AChE homologue neuroligin1, but not the tubulin-associated MAP2 protein. Accompanying BW284C51 effects involved decreases in the Fyn kinase and membrane insertion of the glutamate receptor NR2B variant and impaired glutamatergic activities of treated cells. Intriguingly, molecular modeling suggested that direct, non-catalytic competition with Fyn binding by the RACK1-interacting AChE-R variant may be involved. Conclusions: Our findings highlight complex neuronal AChE-R/RACK1 interactions and are compatible with the hypothesis that peripheral site AChE inhibitors induce RACK1-mediated neuronal remodeling, promoting suppressed glutamatergic neurotransmission.
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© 2007 S. Karger AG, Basel
2007
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