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The Regulatory Mechanism of SNARE Proteins during Epilepsy and Drug Addiction

Author: YuZuoXin
Tutor: PeiGang
School: Shanghai Institutes for Biological Sciences
Course: Cell Biology
Keywords: syntaxin 1A EAAC1 SNAP-25 epilepsy morphine SNARE complex phosphorylation
CLC: R749.64
Type: PhD thesis
Year: 2006
Downloads: 226
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Abstract


Neurotransmitter release plays a central role in neurotransmission. Regulatedmembrane fusion of synaptic vesicles and subsequent transmitter release involve theassembly of ternary complex from soluble N-ethylmaleimide-sensitive factorattachment protein receptor (SNARE) proteins. The ternary complex is formed by thesynaptosomal-associated protein of 25 kDa (SNAP-25) , syntaxin 1A, andvesicle-associated SNARE synaptobrevin 2. The dysfunction in neurotransmissionleads to several neurological disorders, such as epilepsy, drug addiction, Alzheimer’sdisease, Parkinson disease. Here we not only investigate the modulation of SNAREproteins in epilepsy and drug addiction but also provide the molecular and cellularmechanisms shedding light on their therapeutical aspects.(I) The neuronal glutamate transporter, excitatory amino-acid carrier 1 (EAAC1),plays an important role in the modulation of neurotransmission and contributes toepileptogenesis. We further show that syntaxin 1A, a key molecule in synapticexocytosis, potentiates EAAC1 internalization and thus leads to the functionalinhibition of EAAC1. Furthermore, specific suppression of endogenous syntaxin 1Asignificantly blocks the EAAC1 endocytic sorting and lysosomal degradationpromoted by kainic acid, a drug for kindling the animal model of human temporallobe epilepsy, indicating a potential role of syntaxin 1A in epileptogenesis.(II) Here we find that chronic morphine treatment inhibits phosphorylation ofSNAP-25 at Ser187 and leads to dysfunction of SNARE complex formation inhippocampal synaptosomes and PC12 cells. Thus, these results indicate that SNAP-25phosphorylation play a pivotal role in modulation of SNARE complex formationduring drug abuse, which presents a potential molecular mechanism for the alterationof exocytotic process and neural plasticity during opiate abuse.In summary, our work demonstrates that SNARE proteins play a fundamentalrole in the neurological disorders, especially in epilepsy and opiate abuse. Ourfindings provide novel evidences for syntaxin 1A to serve as an intrinsic enhancer toEAAC1 endocytic sorting and thus lead functional inhibition of EAAC1, indicating amolecular mechanism in epileptogenesis. We also reveal that SNARE complexformation and SNAP-25 phosphorylation are inhibited after chronic morphinetreatment in a dose-dependent and time-dependent manner. Taken together, ourobservations shed light on the molecular and neuronal mechanisms underlying theseneurological diseases.

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CLC: > Medicine, health > Neurology and psychiatry > Psychiatry > Mental disorders of toxic
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