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The Journal of Neuroscience, April 30, 2008, 28(18):4702-4711; doi:10.1523/JNEUROSCI.5048-07.2008

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Cellular/Molecular
Connexin 43 Hemichannels Are Permeable to ATP

Jian Kang,¹ Ning Kang,¹ Ditte Lovatt,² Arnulfo Torres,² Zhuo Zhao,¹ Jane Lin,¹ and Maiken Nedergaard²

¹Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York 10595, ²Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642

Correspondence should be addressed to either of the following: Jian Kang, Department of Cell Biology and Anatomy, New York Medical College, 30 Sunshine Cottage Road, Valhalla, NY 10595, Email: Jian_Kang{at}NYMC.edu; or Maiken Nedergaard, Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, Email: Nedergaard{at}URMC.Rochester.edu

Astrocytes are electrically nonexcitable cells that communicate by means of Ca²⁺ signaling. Long-distance intercellular Ca²⁺ waves are initiated by release of ATP and activation of purinergic receptors on nearby cells. Previous studies have implicated connexin 43 (Cx43) in ATP release, but definitive proof that ATP exits through Cx43 hemichannels does not exist. Here, through several alternative approaches, we show that ATP anions can permeate through Cx43 hemichannels. First, openings of Cx43 hemichannels were detected in both cell-attached and inside-out patch recordings in C6 cells expressing Cx43, but not in C6 cells expressing Cx43-eGFP (enhanced green fluorescent protein) or a C-terminus truncation mutant of Cx43. Second, Cx43 hemichannel openings were inhibited by three structurally different gap-junction channel blockers, but not by the P2X₇ blocker Brilliant blue G. Third, bioluminescence imaging of ATP combined with single-channel recording in the inside-out patch configuration showed that ATP efflux coincided with channel openings and was absent when the Cx43 hemichannel was closed. Fourth, ion replacement experiments confirmed that Cx43 hemichannels are permeable to ATP. In summary, these observations provide the first direct evidence for efflux of ATP through Cx43 hemichannels. Furthermore, a putative Cx43 hemichannel with characteristics identical to the Cx43 hemichannel in C6 cells was identified in the membrane of hippocampal astrocytes in acutely prepared slices.

Key words: gap junction; astrocyte; Cx43 hemichannel; bioluminescence; P2X₇; ATP

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Received Nov. 13, 2007; revised March 15, 2008; accepted March 17, 2008.

Correspondence should be addressed to either of the following: Jian Kang, Department of Cell Biology and Anatomy, New York Medical College, 30 Sunshine Cottage Road, Valhalla, NY 10595, Email: Jian_Kang{at}NYMC.edu; or Maiken Nedergaard, Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, Email: Nedergaard{at}URMC.Rochester.edu

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