Two Distinct Heterotypic Channels Mediate Gap Junction Coupling between Astrocyte and Oligodendrocyte Connexins

Orthmann-Murphy, Jennifer; Freidin, Mona M.; Fischer, Elizabeth; Scherer, Steven S.; Abrams, Charles K.

doi:10.1523/jneurosci.3395-07.2007

Cited by 165 publications

(213 citation statements)

References 65 publications

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“…46 By studying the temporal relationship between astrocyte and myelin loss, we showed that astrocyte death precedes demyelination. Connexins connect astrocytes to each other and to oligodendrocytes in a network termed the "glial syncytium," and the integrity of this network is crucial for normal CNS functions, 26,[47][48][49] such as myelination and remyelination upon demyelinative injury. 11,13,25 The importance of the glial syncytium for myelination has been shown in studies utilizing genetic deletions of connexins 43 and 47.…”

Section: Discussionmentioning

confidence: 99%

“…13,25 In the CNS, Cx43 expression is restricted to astrocytes and couples with Cx47, which is only present in oligodendrocytes. 26 Impairment of heterotypic Cx43:Cx47 gap junctions by deleting one of the partners results in myelin pathology 22 . We studied Cx43 gene expression and found that it was substantially downregulated 12 hours after hyponatremia correction (P Ͻ 0.001 compared with controls).…”

Section: Early Downregulation Of Astrocyte-oligodendrocyte Gap Junctimentioning

confidence: 99%

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Astrocytes Are an Early Target in Osmotic Demyelination Syndrome

Kengne

Nicaise²,

Soupart³

et al. 2011

Journal of the American Society of Nephrology

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Abrupt osmotic changes during rapid correction of chronic hyponatremia result in demyelinative brain lesions, but the sequence of events linking rapid osmotic changes to myelin loss is not yet understood. Here, in a rat model of osmotic demyelination syndrome, we found that massive astrocyte death occurred after rapid correction of hyponatremia, delineating the regions of future myelin loss. Astrocyte death caused a disruption of the astrocyte-oligodendrocyte network, rapidly upregulated inflammatory cytokines genes, and increased serum S100B, which predicted clinical manifestations and outcome of osmotic demyelination. These results support a model for the pathophysiology of osmotic brain injury in which rapid correction of hyponatremia triggers apoptosis in astrocytes followed by a loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and finally demyelination.

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Section: Discussionmentioning

confidence: 99%

Section: Early Downregulation Of Astrocyte-oligodendrocyte Gap Junctimentioning

confidence: 99%

Astrocytes Are an Early Target in Osmotic Demyelination Syndrome

Kengne

Nicaise²,

Soupart³

et al. 2011

Journal of the American Society of Nephrology

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“…Astrocytic Cx43 depletion decreases glucose concentration in the extracellular medium and inhibits OPC proliferation, which can be compensated by glucose supply Cx43 is highly expressed by astrocytes, and works as hemichannels and/or homomeric gap junction channels (Cx43-Cx43) between astrocytes (Evans et al, 2013;Mitterauer, 2015;Ransom and Giaume, 2013;Ye et al, 2009), and also forms heteromeric gap junctions (Cx43-Cx47) between astrocytes and oligodendrocytes (Orthmann-Murphy et al, 2007;Theis et al, 2005). It has been reported that in astrocytes, Cx43 deletion increases glucose uptake by a compensatory upregulation of Glut transporters and/or glucose metabolism enzymes (Gangoso et al, 2012).…”

Section: Inhibition Of Hemichannel Activity Impacts Opc Proliferationmentioning

confidence: 99%

Connexin-based channels contribute to metabolic pathways in the oligodendroglial lineage

Niu

et al. 2016

Journal of Cell Science

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Oligodendrocyte precursor cells (OPCs) undergo a series of energyconsuming developmental events; however, the uptake and trafficking pathways for their energy metabolites remain unknown. In the present study, we found that 2-NBDG, a fluorescent glucose analog, can be delivered between astrocytes and oligodendrocytes through connexin-based gap junction channels but cannot be transferred between astrocytes and OPCs. Instead, connexin hemichannel-mediated glucose uptake supports OPC proliferation, and ethidium bromide uptake or increase of 2-NBDG uptake rate is correlated with intracellular Ca 2+ elevation in OPCs, indicating a Ca 2+ -dependent activation of connexin hemichannels. Interestingly, deletion of connexin 43 (Cx43, also known as GJA1) in astrocytes inhibits OPC proliferation by decreasing matrix glucose levels without impacting on OPC hemichannel properties, a process that also occurs in corpus callosum from acute brain slices. Thus, dual functions of connexin-based channels contribute to glucose supply in oligodendroglial lineage, which might pave a new way for energymetabolism-directed oligodendroglial-targeted therapies.

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“…18,19 The O/A coupling is mediated by heterotypic channels between CÂ47/CÂ43 and CÂ32/CÂ30, both appearing to be essential for the proper maintenance of myelin. 20 So far, CÂ47 mutants have been shown to result in loss of function, suggesting an impaired O/A coupling mediated by CÂ47/CÂ43. 21 Here, we provide further evidence that loss of CÂ47 function causes PMLD.…”

Section: Introductionmentioning

confidence: 99%

Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

et al. 2010

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Autosomal recessive mutations in the GJA12/GJC2 gene encoding the gap junction protein connexin47 (CÂ47) cause a form of Pelizaeus-Merzbacher-like disease (PMLD) with hypomyelination, nystagmus, impaired psychomotor development and progressive spasticity. We investigated the functional consequences of four CÂ47 missense mutations (G149S, G236R, T265A, and T398I) and one CÂ47 complex mutation (A98G_V99insT) by immunoblot analysis and immunocytochemistry in transfected communication-incompetent HeLa cells and in OLI-neu cells. All studied CÂ47 mutants, except G236R, generated stable proteins in transfected HeLa cells and OLI-neu cells. The mutants T265A and A98G_V99insT were retained in the ER, T398I formed gap junctional plaques at the plasma membrane, and G149S showed both, structures at the plasma membrane and ER localization. Two-microelectrode voltage clamp analyses in Xenopus laevis oocytes injected with wild-type and mutant CÂ47 cRNA revealed reduced hemichannel currents for G236R, T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wild-type. For CÂ47 mutant T398I, our results indicate a defect in hemichannel function, whereas CÂ47 mutants G149S, G236R, T265A, and A98G_V99insT are predicted to result in a loss of CÂ47 hemichannel function. Thus, PMLD is likely to be caused by two different disease mechanisms: a loss of function and a dysfunction.

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Two Distinct Heterotypic Channels Mediate Gap Junction Coupling between Astrocyte and Oligodendrocyte Connexins

Abstract: Genetic diseases demonstrate that the normal function of CNS myelin depends on connexin32 (

Cited by 165 publications

References 65 publications

Astrocytes Are an Early Target in Osmotic Demyelination Syndrome

Astrocytes Are an Early Target in Osmotic Demyelination Syndrome

Connexin-based channels contribute to metabolic pathways in the oligodendroglial lineage

Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

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