Connexin and pannexin hemichannels in inflammatory responses of glia and neurons

Michael V. L. Bennett, Juan M. Garré, Juan A. Orellana, Felix F. Bukauskas, Maiken Nedergaard, Juan C. Sáez

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Mammals express ∼20 different connexins, the main gap junction forming proteins in mammals, and 3 pannexins, homologs of innexins, the main gap junction forming proteins in invertebrates. In both classes of gap junction, each channel is formed by two hemichannels, one contributed by each of the coupled cells. There is now general, if not universal, agreement that hemichannels of both classes can open in response to various physiological and pathological stimuli when they are not apposed to another hemichannels and face the external milieu. Connexin (and likely pannexin) hemichannel permeability is consistent with that of the cell-cell channels and open hemichannels can be a release site for relatively large molecules such as ATP and glutamate, which can serve as transmitters between cells. Here we describe three experimental paradigms in which connexin and pannexin hemichannel signaling occurs. (1) In cultures of spinal astrocytes FGF-1 causes the release of ATP, and ATP causes opening of pannexin hemichannels, which then release further ATP. Subsequently, several hours later, connexin hemichannels are also opened by an unknown mechanism. Release of ATP appears to become self sustaining through action of P2X7 receptors to open pannexin hemichannels and then connexin hemichannels, both of which are ATP permeable. (2) Spinal cord injury by dropping a small weight on the exposed cord is followed by release of ATP in the region surrounding the primary lesion. This release is greatly reduced in a mouse in which Cx43 is knocked down in the astrocytes. Application of FGF-1 causes a similar release of ATP in the uninjured spinal cord, and an inhibitor of the FGF-1 receptor, PD173074, inhibits both FGF-1 and injury-induced release. Reduction in ATP release is associated with reduced inflammation and less secondary expansion of the lesion. (3) Cortical astrocytes in culture are permeabilized by hypoxia, and this effect is increased by high or zero glucose. The mechanism of permeabilization is opening of Cx43 hemichannels, which can lead to cell death. Activated microglia secrete TNF-α and IL-1β, which open connexin hemichannels in astrocytes. Astrocytes release ATP and glutamate which can kill neurons in co-culture through activation of neuronal pannexin hemichannels. These studies implicate two kinds of gap junction hemichannel in inflammatory responses and cell death. This article is part of a Special Issue entitled Electrical Synapses.

Original languageEnglish (US)
Pages (from-to)3-15
Number of pages13
JournalBrain Research
Volume1487
DOIs
StatePublished - Dec 3 2012

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Connexins
Neuroglia
Adenosine Triphosphate
Neurons
Fibroblast Growth Factor 1
Astrocytes
Connexin 43
Gap Junctions
Glutamic Acid
Mammals
Cell Death
Electrical Synapses
Purinergic P2X7 Receptors
Fibroblast Growth Factor Receptors
Microglia
Invertebrates
Coculture Techniques
Spinal Cord Injuries
Interleukin-1
Permeability

Keywords

  • Astrocyte
  • Connexin
  • Connexon
  • FGF-1
  • Hemichannel
  • Inflammation
  • Microglia
  • Neuronal death
  • Pannexin
  • Pannexon

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Bennett, M. V. L., Garré, J. M., Orellana, J. A., Bukauskas, F. F., Nedergaard, M., & Sáez, J. C. (2012). Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Research, 1487, 3-15. https://doi.org/10.1016/j.brainres.2012.08.042

Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. / Bennett, Michael V. L.; Garré, Juan M.; Orellana, Juan A.; Bukauskas, Felix F.; Nedergaard, Maiken; Sáez, Juan C.

In: Brain Research, Vol. 1487, 03.12.2012, p. 3-15.

Research output: Contribution to journalArticle

Bennett, MVL, Garré, JM, Orellana, JA, Bukauskas, FF, Nedergaard, M & Sáez, JC 2012, 'Connexin and pannexin hemichannels in inflammatory responses of glia and neurons', Brain Research, vol. 1487, pp. 3-15. https://doi.org/10.1016/j.brainres.2012.08.042
Bennett, Michael V. L. ; Garré, Juan M. ; Orellana, Juan A. ; Bukauskas, Felix F. ; Nedergaard, Maiken ; Sáez, Juan C. / Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. In: Brain Research. 2012 ; Vol. 1487. pp. 3-15.
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