Functional Hemichannels in Astrocytes: A Novel Mechanism of Glutamate Release

Ye, Zu Cheng; Wyeth, Megan S.; Baltan-Tekkok, Selva; Ransom, Bruce R.

doi:10.1523/jneurosci.23-09-03588.2003

Cited by 647 publications

(599 citation statements)

References 58 publications

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“…Under some culture conditions, low extracellular Ca 2+ levels cause release of glutamate from astrocytes, evidently by opening of hemichannels (as evidenced by sensitivity to gap-junction blockers and dye uptake [32]). What is striking about these observations is that significant release was observed at Ca 2+ levels that might well occur under conditions of ischemia, seizures or spreading depression.…”

Section: Hemichannels In the Cnsmentioning

confidence: 99%

“…Low Ca 2+ levels alone appear to cause hemichannel opening in astrocytes. One study indicates that significant opening can occur in astrocytes at low but not unreasonable external Ca 2+ concentrations [32], whereas another study sees little effect at nominally zero Ca 2+ [14]; the differences in these studies might arise from differences in culture conditions. Metabolic inhibition and ischemia can increase hemichannel opening.…”

mentioning

confidence: 99%

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New roles for astrocytes: Gap junction hemichannels have something to communicate

Bennett

Contreras

Bukauskas

et al. 2003

Trends in Neurosciences

375

279

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Gap junctions are clusters of aqueous channels that connect the cytoplasm of adjoining cells. Each cell contributes a hemichannel, or connexon, to each cell-cell channel. The cell-cell channels are permeable to relatively large molecules, and it was thought that opening of hemichannels to the extracellular space would kill cells through loss of metabolites, collapse of ionic gradients and influx of Ca 2+ . Recent findings indicate that specific non-junctional hemichannels do open under both physiological and pathological conditions, and that opening is functional or deleterious depending on the situation. Most of these studies utilized cells in tissue culture that expressed a specific gap junction protein, connexin 43. Several such examples are reviewed here, with a particular focus on astrocytes.Gap junctions mediate intercellular communication by providing ultrastructural cytoplasmic continuity, and they are integral to formation of the functional syncytium of astrocytes. Each of the joined cells contributes a hemichannel or connexon to each cell-cell channel ( Figure 1; Box 1). Each hemichannel comprises a hexamer of connexins arranged around a central pore, and the cell-cell channels are gated by several stimuli, including transjunctional voltage, low pH and various pharmacological agents. Connexins are encoded by a gene family with at least 20 members in mammals [1].Gap-junction pores are nominally 1.0-1.5 nm in diameter and are permeable to molecules of 1 kDa [2]. Junctions formed from connexin 43 (Cx43), the predominant connexin in astrocytes, are permeable to Lucifer Yellow (443 Da, −2 charge) and propidium (420 Da, +2 charge). Other connexins appear to be more charge selective: Cx32 is more permeable to anions and Cx45 is more permeable to cations [2]. Single-channel conductance varies widely, from ~15 pS for Cx36 [3] and 110 pS for Cx43 [4] to ~375 pS for Cx37 [5]. The maximum size of permeant species also varies. Such diversity in selectivity and conductance are likely to account for the expansion of the connexin family. Why shouldn't hemichannels be open?Given the permeability and conductance of gap junctions, and the expectation that an open hemichannel would have twice the conductance and permeability of a cell-cell channel (in terms of ion or molecular flux, rather than selectivity), it was thought unlikely that hemichannels in the non-junctional membrane would open [6]. Direct evidence for this was provided by measurements during formation of the first channel between a newly apposed pair of cells. Each cell was held at a different potential, and then when the first channel NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript opened, increased current was seen in the cell held at a more positive potential and decreased (more negative) current was seen in the other cell, but the sum of the currents clamping the two cells remained constant [7]. Thus, there was no change in the current flowing into the extracellular space, and the hemichannels were closed before openin...

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Section: Hemichannels In the Cnsmentioning

confidence: 99%

mentioning

confidence: 99%

New roles for astrocytes: Gap junction hemichannels have something to communicate

Bennett

Contreras

Bukauskas

et al. 2003

Trends in Neurosciences

375

279

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“…The underlying mechanism is currently unknown, but the phenomena is consistent with the expression of these receptors in glia and may have considerable clinical significance. Hemi-channels Low extracellular divalent ion (Ye et al, 2003). Subunit mRNA transcripts that are strongly present are marked "++", transcripts that are present are marked "+" and subunits that are absent are marked " -".…”

Section: Figure 3 Near Herementioning

confidence: 99%

Glia as transmitter sources and sensors in health and disease

Domingues

Taylor

Fern

2010

Neurochemistry International

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Glial cells express a bewildering array of neurotransmitter receptors. To illustrate the complexity of expression, we have assayed non-glutamatergic neurotransmitter receptor mRNA in isolated rat optic nerve, a preparation devoid of neurons and neuronal synapses and from which relatively pure "glial" RNA can be isolated. Of the 44 receptor subunits examined which span the GABA-A, nicotinic, adreno-and glycine receptor families, over three quarters were robustly expressed in this mixed population of white matter glial cells, with several expressed at higher levels than found in control whole brain RNA. In addition to the complexity of glial receptor expression, numerous neurotransmitter release mechanisms have been identified. We have focused on glutamate release from astrocytes, which can occur via at least seven distinct pathways and which is implicated in excitotoxic injury of neurons and glia. Recent findings suggesting that non-glutamatergic receptors can also mediate acute glial injury are also discussed.3

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“…Cx43 hemichannels have been considered responsible for dye uptake and increased cell death upon metabolic inhibition of astrocytes (6) and cardiac myocytes (7). Additionally, Cx43 hemichannels have been reported to provide pores for ATP release (8) as well as glutamate and aspartate efflux in astrocytes (9). These divergent functions attributed to gap junctional hemichannels are controversial (10), since some of these effects are now attributable to other types of channels and can also be elicited from astrocytes in Cx43 nullmutant animals.…”

Section: Introductionmentioning

confidence: 99%

Following Tracks of Hemichannels

Dermietzel

Meier

Bukauskas

et al. 2003

Cell Communication & Adhesion

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It has been suggested that plasma membrane-bound hemichannels perform physiological and pathophysiological functions per se. Such functions require the presence of hemichannels on the cell surface and their accessibility to the extracellular environment for at least some limited period of time. We have previously shown that hemichannels can be labeled by means of antibodies directed to an external loop domain of connexin (Cx) 43 (1). We now provide evidence that trafficking of hemichannel vesicles can be visualized upon binding of a labeled homophilic peptide corresponding to a region of the first extracellular loop (EL1) of Cx43.In vivo imaging was performed after labeling hemichannels from the extracellular site with a mimetic peptide tagged with a fluorochrome (Alexa-546). Using a Cx43-CFP transfected HeLa cell line for incubation with the mimetic peptide, a significant number of double-labeled vesicles were found inside the cells. This double labeling indicates that a portion of Cx43 within the cell had accessed the cell surface as hemichannels where it bound to the peptide and was subsequently endocytosed. Pulse labeling with the peptide showed a decrease in the number of dual-labeled vesicles over time, indicating degradation and/or concurrent recycling of hemichannel vesicles.

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Functional Hemichannels in Astrocytes: A Novel Mechanism of Glutamate Release

Cited by 647 publications

References 58 publications

New roles for astrocytes: Gap junction hemichannels have something to communicate

New roles for astrocytes: Gap junction hemichannels have something to communicate

Glia as transmitter sources and sensors in health and disease

Following Tracks of Hemichannels

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