ATP released from astrocytes during swelling activates chloride channels

J Neurophysiol. 2003 Apr;89(4):1870-7. doi: 10.1152/jn.00510.2002.


ATP release from astrocytes contributes to calcium ([Ca(2+)]) 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 (I(Cl,swell)) through an autocrine pathway involving purinergic receptors. Astrocyte swelling is counterbalanced by a regulatory volume decrease, involving efflux of metabolites and activation of I(Cl,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 I(Cl,swell) by hypo-osmotic solution (HOS). Apyrase, an ATP/ADP nucleotidase, inhibited HOS-activated I(Cl,swell), whereas ATP and the P2Y agonists, ADPbetaS and ADP, induced Cl(-) currents similar to I(Cl,swell). Neither the P2U agonist, UTP nor the P2X agonist, alpha,beta-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 I(Cl,swell), suggesting that ATP-activated P2Y1 receptors. Thus ATP release mediates I(Cl,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 I(Cl.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 I(Cl,swell) in astrocytes by HOS-induced swelling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apyrase / metabolism
  • Astrocytes / metabolism*
  • Cells, Cultured
  • Chloride Channels / metabolism*
  • Chlorides / metabolism
  • Hypotonic Solutions / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Platelet Aggregation Inhibitors / pharmacology
  • Probenecid / pharmacology
  • Purinergic P2 Receptor Antagonists
  • Pyridoxal Phosphate / analogs & derivatives*
  • Pyridoxal Phosphate / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2 / metabolism
  • Suramin / pharmacology
  • Uricosuric Agents / pharmacology
  • Water-Electrolyte Balance / drug effects
  • Water-Electrolyte Balance / physiology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Chloride Channels
  • Chlorides
  • Hypotonic Solutions
  • Platelet Aggregation Inhibitors
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2
  • Uricosuric Agents
  • pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid
  • Pyridoxal Phosphate
  • Suramin
  • Adenosine Triphosphate
  • Apyrase
  • Probenecid