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The Journal of Neuroscience, February 15, 2003, 23(4):1320

P2X₇ Receptor-Mediated Release of Excitatory Amino Acids from Astrocytes

Shumin Duan¹, Christopher M. Anderson¹, Edmund C. Keung², Yongmei Chen¹, Yiren Chen¹, and Raymond A. Swanson¹

Departments of ¹ Neurology and ² Medicine, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121

Astrocyte glutamate release can modulate synaptic activity and participate in brain intercellular signaling. P2X₇ receptors form large ion channels when activated by ATP or other ligands. Here we show that P2X₇ receptors provide a route for excitatory amino acid release from astrocytes. Studies were performed using murine cortical astrocyte cultures. ATP produced an inward current in patch-clamped astrocytes with properties characteristic of P2X₇ receptor activation: the current was amplified in low divalent cation medium, blocked by pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and more potently activated by 3'-O-(4-benzoyl)benzoyl ATP (BzATP) than by ATP itself. Measurement of current reversal potentials showed the relative BzATP-induced permeabilities to different substrates to be Na⁺, 1 > Cl, 0.34 > N-methyl-D-glucamine, 0.27 > L-glutamate, 0.15  D-aspartate, 0.16. Astrocytes exposed to BzATP also became permeable to Lucifer yellow, indicating a large channel opening. Release of L-glutamate and D-aspartate through P2X₇ channels was confirmed using radiolabeled tracers. As with the inward current, release of glutamate and D-aspartate was induced by BzATP more potently than ATP, amplified in Ca²⁺/Mg²⁺-free medium, and blocked by PPADS or oxidized ATP. Efflux through P2X₇ channels is a previously unrecognized route of ligand-stimulated, nonvesicular astrocyte glutamate release.

Key words: D-aspartate; glutamate; P2Z; patch clamp; nonvesicular; purinergic

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2341320-09$05.00/0

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