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J. Biol. Chem., Vol. 281, Issue 41, 30684-30696, October 13, 2006

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P2Y1 Receptor-evoked Glutamate Exocytosis from Astrocytes

CONTROL BY TUMOR NECROSIS FACTOR- AND PROSTAGLANDINS^*

Maria Domercq¹, Liliana Brambilla, Ethel Pilati, Julie Marchaland, Andrea Volterra, and Paola Bezzi²

From the Department of Cell Biology and Morphology, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland and the Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy

ATP, released by both neurons and glia, is an important mediator of brain intercellular communication. We find that selective activation of purinergic P2Y1 receptors (P2Y1R) in cultured astrocytes triggers glutamate release. By total internal fluorescence reflection imaging of fluorescence-labeled glutamatergic vesicles, we document that such release occurs by regulated exocytosis. The stimulus-secretion coupling mechanism involves Ca²⁺ release from internal stores and is controlled by additional transductive events mediated by tumor necrosis factor- (TNF) and prostaglandins (PG). P2Y1R activation induces release of both TNF and PGE₂ and blocking either one significantly reduces glutamate release. Accordingly, astrocytes from TNF-deficient (TNF^–/–) or TNF type 1 receptor-deficient (TNFR1^–/–) mice display altered P2Y1R-dependent Ca²⁺ signaling and deficient glutamate release. In mixed hippocampal cultures, the P2Y1R-evoked process occurs in astrocytes but not in neurons or microglia. P2Y1R stimulation induces Ca²⁺-dependent glutamate release also from acute hippocampal slices. The process in situ displays characteristics resembling those in cultured astrocytes and is distinctly different from synaptic glutamate release evoked by high K⁺ stimulation as follows: (a) it is sensitive to cyclooxygenase inhibitors; (b) it is deficient in preparations from TNF^–/– and TNFR1^–/– mice; and (c) it is inhibited by the exocytosis blocker bafilomycin A1 with a different time course. No glutamate release is evoked by P2Y1R-dependent stimulation of hippocampal synaptosomes. Taken together, our data identify the coupling of purinergic P2Y1R to glutamate exocytosis and its peculiar TNF- and PG-dependent control, and we strongly suggest that this cascade operates selectively in astrocytes. The identified pathway may play physiological roles in glial-glial and glial-neuronal communication.

Received for publication, July 6, 2006

^* This work was supported in part by Swiss FNRS Grant 3100A0-100850/1, OFES Grant 00.0553, Italian MIUR Cofin 2002 and FIRB 2003, and CARIPLO (to A. V.). 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.

¹ Recipient of a postdoctoral fellowship from the Basque Government. Present address: Dept. of Neurosciences, Faculty of Medicine, University of the Basque Country, 48640 Leioa, Vizcaya, Spain.

² To whom correspondence should be addressed. Tel.: 41-21-692-5284; Fax: 41-21-692-5105; E-mail: Paola.Bezzi{at}unil.ch.

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