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J. Biol. Chem., Vol. 281, Issue 38, 28174-28184, September 22, 2006

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SNAP-25/Syntaxin 1A Complex Functionally Modulates Neurotransmitter -Aminobutyric Acid Reuptake^*

Hua-Ping Fan, Feng-Juan Fan, Lan Bao¹, and Gang Pei²

From the Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and the Graduate School of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China

Neurotransmitter -aminobutyric acid (GABA) release to the synaptic clefts is mediated by the formation of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which includes two target SNAREs syntaxin 1A and SNAP-25 and one vesicle SNARE VAMP-2. The target SNAREs syntaxin 1A and SNAP-25 form a heterodimer, the putative intermediate of the SNARE complex. Neurotransmitter GABA clearance from synaptic clefts is carried out by the reuptake function of its transporters to terminate the postsynaptic signaling. Syntaxin 1A directly binds to the neuronal GABA transporter GAT-1 and inhibits its reuptake function. However, whether other SNARE proteins or SNARE complex regulates GABA reuptake remains unknown. Here we 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 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. Furthermore, nitric oxide, which promotes SNAP-25 binding to syntaxin 1A to form the 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 a target SNARE complex and suggest a direct coordination between GABA release and reuptake.

Received for publication, February 13, 2006 , and in revised form, May 30, 2006.

^* This work was supported by the Ministry of Science and Technology Grants 2003CB515405 and 2005CB522406 and the National Natural Science Foundation of China Grants 30021003 and 30325024. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence may be addressed. Tel.: 86-21-54921369; Fax: 86-21-54921762; E-mail: baolan{at}sibs.ac.cn.

² To whom correspondence may be addressed. Tel.: 86-21-54921371; Fax: 86-21-54921011; E-mail: gpei{at}sibs.ac.cn.

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