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J. Biol. Chem., Vol. 279, Issue 39, 40601-40608, September 24, 2004

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Inhibition of SNAP-25 Phosphorylation at Ser¹⁸⁷ Is Involved in Chronic Morphine-induced Down-regulation of SNARE Complex Formation^*

Nan-Jie Xu¶, Yong-Xin Yu, Jian-Mei Zhu, Hua Liu, Li Shen, Rong Zeng, Xu Zhang||, and Gang Pei**

From the Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, ^||Laboratory of Sensory System, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, People's Republic of China

Opiate abuse has been shown to cause adaptive changes in presynaptic release and protein phosphorylation-mediated synaptic plasticity, but the underlying mechanisms remain unclear. Neuronal SNARE proteins serve as important regulatory molecules underlying neural plasticity in view of their major role in the process of neurotransmitter release. In the present study, the expression of SNAP-25, a t-SNARE protein essential for vesicle release, was found to be dramatically regulated in hippocampus after chronic morphine treatment, which was visualized with two-dimensional gel electrophoresis. The spots of SNAP-25 in the gel were shifted along the dimension of isoelectric point, indicating a likely change of the post-transcriptional modification. Immunoblotting analysis with specific antibody to Ser¹⁸⁷, a protein kinase C (PKC) phosphorylation site of SNAP-25, revealed that the specific phosphorylation was correspondingly decreased, which was correlated with morphine-induced inhibition of PKC activity. Moreover, the level of ternary complex of SNARE proteins in either synaptosomes or PC12 cells was significantly reduced after chronic morphine treatment. This suggests a causal relationship between the inhibition of PKC-dependent SNAP-25 phosphorylation and the down-regulation of SNARE complex formation after chronic morphine treatment. Further analysis of SNARE complex formed by transfection of the wild-type or Ser¹⁸⁷ mutants of SNAP-25 showed that only wild-type-formed complex was inhibited by morphine treatment. Thus, these results indicate that chronic morphine treatment inhibits phosphorylation of SNAP-25 at Ser¹⁸⁷ and leads to a down-regulation of SNARE complex formation, which presents a potential molecular mechanism for the alteration of exocytotic process and neural plasticity during opiate abuse.

Received for publication, June 21, 2004 , and in revised form, July 19, 2004.

^* This work was supported by the Ministry of Science and Technology (Grants G1999053907, G2000077800, and 2003CB515405), the Chinese Academy of Sciences (Grants KSCX1-SW-11 and KSCX2-SW-204), the National Natural Science Foundation of China (Grants 30021003 and 30321002), the Shanghai Science and Technology Committee (Grants 03DZ19213 and 018014015), and the K. C. Wong Education Foundation of Hong Kong. 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.

Both authors contributed equally to this work.

^¶ Present address: University of Texas Southwestern Medical Center, Dallas, TX 75235

^** To whom correspondence should be addressed. Tel.: 86-21-5492-1371; Fax: 86-21-5492-0078, E-mail: gpei{at}sibs.ac.cn.

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