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SNARE Complex Involved in Neurotransmitter Release Functionally Modulates Neurotransmitter GABA Reuptake

Author: FanHuaPing
Tutor: PeiGang
School: Shanghai Institutes for Biological Sciences
Course: Cell Biology
Keywords: target-SNARE complex SNAP-25 syntaxin 1A GABA transporter GAT-1
CLC: Q42
Type: PhD thesis
Year: 2006
Downloads: 204
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Neurotransmitter release to synaptic clefts is mediated by the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. The ternary complex is composed of two plasma membrane proteins including syntaxin 1A and synaptosomal-associated protein of 25 kDa (SNAP-25), which are called target-SNAREs (t-SNAREs), and one vesicle-associated protein synaptobrevin 2 (VAMP-2), which is called vesicle-SNARE (v-SNARE). The target-SNAREs syntaxin 1A and SNAP-25 form a heterodimer, the putative intermediate of SNARE complex which is called target-SNARE complex, and offers target sites for the vesicle-SNARE VAMP-2 binding to form SNARE complex. The major inhibitory neurotransmitterγ-aminobutyric acid (GABA) is released from presynaptic terminals to synaptic clefts by this means. GABA in synaptic clefts binds to postsynaptic GABA receptors and thus transmits the signal to the postsynaptic terminals. Neurotransmitter GABA clearance from synaptic clefts is carried out by the reuptake function of its transporters to terminate the postsynaptic signaling. It has been reported that the target-SNARE syntaxin 1A directly binds to the neuronal GABA transporter GAT-1 (GABA transporter-1) subtype and inhibits its reuptake function. However, whether other SNARE proteins or SNARE complex regulates GABA reuptake remains unknown. Here we investigated the mechanism for the regulation of GAT-1 by the SNARE complex using molecular cloning methods, GABA uptake detection, immunocytochemistry, coimmunoprecipitation and fluorescence resonance energy transfer (FRET) measurements and so on. Our results demonstrate that SNAP-25 efficiently inhibits GAT-1 reuptake function in the presence of syntaxin 1A. This inhibition depends on SNAP-25/syntaxin 1A complex (target-SNARE complex) formation. The H3 domain of syntaxin 1A is identified as the binding sites for both SNAP-25 and GAT-1. SNAP-25 binding to syntaxin 1A greatly potentiates the physical interaction of syntaxin 1A with GAT-1 and significantly enhances the syntaxin 1A-mediated inhibition of GAT-1 reuptake function. Meanwhile, we found that the vesicle-SNARE VAMP-2 binding to the target-SNARE complex does not affect the inhibition of GAT-1 reuptake function by the target-SNARE complex. Furthermore, nitric oxide, which promotes SNAP-25 binding to syntaxin 1A to form SNARE complex, also potentiates the interaction of syntaxin 1A with GAT-1 and suppresses GABA reuptake by GAT-1. Thus our findings delineate a further molecular mechanism for the regulation of GABA reuptake by the target-SNARE complex and suggest a direct coordination between GABA release and reuptake.

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CLC: > Biological Sciences > Physiology > Neurophysiology
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