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J Neurophysiol (April 1, 2003). 10.1152/jn.00510.2002
Submitted on Submitted 3 July 2002; accepted in final form 6 June 2002
Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Darby, Mark,
J. Brent Kuzmiski,
William Panenka,
Denise Feighan, and
Brian A. MacVicar.
ATP Released From Astrocytes During Swelling Activates Chloride
Channels. J. Neurophysiol. 89: 1870-1877, 2003. ATP release from astrocytes contributes to calcium
([Ca2+]) wave propagation and may modulate
neuronal excitability. In epithelial cells and hepatocytes, cell
swelling causes ATP release, which leads to the activation of a
volume-sensitive Cl
current
(ICl,swell) through an autocrine
pathway involving purinergic receptors. Astrocyte swelling is
counterbalanced by a regulatory volume decrease, involving efflux of
metabolites and activation of
ICl,swell and K+
currents. We used whole cell patch-clamp recordings in cultured astrocytes to investigate the autocrine role of ATP in the activation of ICl,swell by hypo-osmotic solution
(HOS). Apyrase, an ATP/ADP nucleotidase, inhibited HOS-activated
ICl,swell, whereas ATP and the P2Y
agonists, ADP
S and ADP, induced Cl currents
similar to ICl,swell. Neither the P2U
agonist, UTP nor the P2X agonist, 
,-methylene ATP, were
effective. BzATP was less effective than ATP, suggesting that P2X7
receptors were not involved. P2 purinergic antagonists, suramin, RB2,
and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid
(PPADS) reversibly inhibited activation of
ICl,swell, suggesting that
ATP-activated P2Y1 receptors. Thus ATP release mediates
ICl,swell in astrocytes through the
activation of P2Y1-like receptors. The multidrug resistance protein
(MRP) transport inhibitors probenicid, indomethacin, and MK-571 all
potently inhibited ICl.swell. ATP release from astrocytes in HOS was observed directly using
luciferin-luciferase and MK-571 reversibly depressed this HOS-induced
ATP efflux. We conclude that ATP release via MRP and subsequent
autocrine activation of purinergic receptors contributes to the
activation of ICl,swell in astrocytes
by HOS-induced swelling.
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