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J. Biol. Chem., Vol. 282, Issue 33, 24185-24197, August 17, 2007

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Glutamate-induced Exocytosis of Glutamate from Astrocytes^*

Jun Xu, Hong Peng, Ning Kang, Zhuo Zhao^¶, Jane H-C. Lin, Patric K. Stanton, and Jian Kang¹

From the Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York 10595, the Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institutes, University of Texas Southwestern Medical Center, Dallas Texas 75390, and the ^¶Department of Physiology, China Medical University, 110001 Shenyang, China

Recent studies indicate that astrocytes can play a much more active role in neuronal circuits than previously believed, by releasing neurotransmitters such as glutamate and ATP. Here we report that local application of glutamate or glutamine synthetase inhibitors induces astrocytic release of glutamate, which activates a slowly decaying transient inward current (SIC) in CA1 pyramidal neurons and a transient inward current in astrocytes in hippocampal slices. The occurrence of SICs was accompanied by an appearance of large vesicles around the puffing pipette. The frequency of SICs was positively correlated with [glutamate]_o. EM imaging of anti-glial fibrillary acid protein-labeled astrocytes showed glutamate-induced large astrocytic vesicles. Imaging of FM 1-43 fluorescence using two-photon laser scanning microscopy detected glutamate-induced formation and fusion of large vesicles identified as FM 1-43-negative structures. Fusion of large vesicles, monitored by collapse of vesicles with a high intensity FM 1-43 stain in the vesicular membrane, coincided with SICs. Glutamate induced two types of large vesicles with high and low intravesicular [Ca²⁺]. The high [Ca²⁺] vesicle plays a major role in astrocytic release of glutamate. Vesicular fusion was blocked by infusing the Ca²⁺ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, or the SNARE blocker, tetanus toxin, suggesting Ca²⁺- and SNARE-dependent fusion. Infusion of the vesicular glutamate transport inhibitor, Rose Bengal, reduced astrocytic glutamate release, suggesting the involvement of vesicular glutamate transports in vesicular transport of glutamate. Our results demonstrate that local [glutamate]_o increases induce formation and exocytotic fusion of glutamate-containing large astrocytic vesicles. These large vesicles could play important roles in the feedback control of neuronal circuits and epileptic seizures.

Received for publication, January 16, 2007 , and in revised form, June 18, 2007.

^* This work was supported by National Institute of Health Grant NS 39997. 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 Movies 1–3.

¹ To whom correspondence should be addressed: Dept. of Cell Biology and Anatomy, New York Medical College, Basic Science Bldg., Rm. 220, Valhalla, NY 10595. Tel.: 914-594-3156; Fax: 914-594-4653; E-mail: jian_kang{at}NYMC.edu.

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