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Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases.

Takeuchi H, Suzumura A - Front Cell Neurosci (2014)

Bottom Line: The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects.We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface.Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University Nagoya, Japan.

ABSTRACT
Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g., minocycline) have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

Mechanism of glutamate production and release by activated microglia. Like other types of cells, resting microglia use glutamate dehydrogenase to synthesize glutamate from intracellular α-ketoglutarate in order to maintain a physiologically normal level of glutamate. Under resting conditions, microglia release very little glutamate into the extracellular space. By contrast, under pathological conditions, glutaminase and gap-junction hemichannels are upregulated in activated microglia (e.g., in response to stimulation by TNF-α). Glutaminase synthesizes excess glutamate from extracellular glutamine, which is brought into the cell via glutamine transporters. Subsequently, high levels of glutamate are secreted through gap-junction hemichannels, resulting in eventual neuronal damage.
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Figure 1: Mechanism of glutamate production and release by activated microglia. Like other types of cells, resting microglia use glutamate dehydrogenase to synthesize glutamate from intracellular α-ketoglutarate in order to maintain a physiologically normal level of glutamate. Under resting conditions, microglia release very little glutamate into the extracellular space. By contrast, under pathological conditions, glutaminase and gap-junction hemichannels are upregulated in activated microglia (e.g., in response to stimulation by TNF-α). Glutaminase synthesizes excess glutamate from extracellular glutamine, which is brought into the cell via glutamine transporters. Subsequently, high levels of glutamate are secreted through gap-junction hemichannels, resulting in eventual neuronal damage.

Mentions: Recent studies have revealed the precise mechanism of glutamate production by activated microglia (Takeuchi et al., 2005, 2006) (Figure 1). Two pathways are involved in cellular glutamate synthesis (Newsholme and Newsholme, 1989; Newsholme and Calder, 1997; Yudkoff, 1997; Nissim, 1999). One of these pathways is mediated by glutamate dehydrogenase, which converts α-ketoglutarate to glutamate. Most cells use this pathway to maintain cellular homeostasis of glutamate levels. The other pathway is mediated by glutaminase, which produces glutamate from extracellular glutamine brought into the cell via glutamine transporters. Resting microglia maintain their physiological glutamate level via the glutamate dehydrogenase pathway, as in other cell types, and secrete very little glutamate into the extracellular space (Figure 1). By contrast, activated microglia produce excessive amounts of glutamate as a result of upregulation of glutaminase, but not glutamate dehydrogenase. Subsequently, activated microglia release massive amounts of glutamate via gap-junction hemichannels. Inflammatory cytokines such as TNF-α and IFN-γ enhance not only glutaminase expression level but also cell-surface localization of hemichannels in microglia (Eugenin et al., 2001; Takeuchi et al., 2006). These two phenomena may act synergistically to release excess glutamate, leading to excitotoxic neuronal damage (Figure 1). Moreover, the extracellular glutamine level is critical for microglial glutamate production (Takeuchi et al., 2006). In the CNS, glutamine from astrocytes is essential for glutamate production in neurons (Tsacopoulos and Magistretti, 1996), suggesting that it also plays an important role in microglial glutamate production.


Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases.

Takeuchi H, Suzumura A - Front Cell Neurosci (2014)

Mechanism of glutamate production and release by activated microglia. Like other types of cells, resting microglia use glutamate dehydrogenase to synthesize glutamate from intracellular α-ketoglutarate in order to maintain a physiologically normal level of glutamate. Under resting conditions, microglia release very little glutamate into the extracellular space. By contrast, under pathological conditions, glutaminase and gap-junction hemichannels are upregulated in activated microglia (e.g., in response to stimulation by TNF-α). Glutaminase synthesizes excess glutamate from extracellular glutamine, which is brought into the cell via glutamine transporters. Subsequently, high levels of glutamate are secreted through gap-junction hemichannels, resulting in eventual neuronal damage.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151093&req=5

Figure 1: Mechanism of glutamate production and release by activated microglia. Like other types of cells, resting microglia use glutamate dehydrogenase to synthesize glutamate from intracellular α-ketoglutarate in order to maintain a physiologically normal level of glutamate. Under resting conditions, microglia release very little glutamate into the extracellular space. By contrast, under pathological conditions, glutaminase and gap-junction hemichannels are upregulated in activated microglia (e.g., in response to stimulation by TNF-α). Glutaminase synthesizes excess glutamate from extracellular glutamine, which is brought into the cell via glutamine transporters. Subsequently, high levels of glutamate are secreted through gap-junction hemichannels, resulting in eventual neuronal damage.
Mentions: Recent studies have revealed the precise mechanism of glutamate production by activated microglia (Takeuchi et al., 2005, 2006) (Figure 1). Two pathways are involved in cellular glutamate synthesis (Newsholme and Newsholme, 1989; Newsholme and Calder, 1997; Yudkoff, 1997; Nissim, 1999). One of these pathways is mediated by glutamate dehydrogenase, which converts α-ketoglutarate to glutamate. Most cells use this pathway to maintain cellular homeostasis of glutamate levels. The other pathway is mediated by glutaminase, which produces glutamate from extracellular glutamine brought into the cell via glutamine transporters. Resting microglia maintain their physiological glutamate level via the glutamate dehydrogenase pathway, as in other cell types, and secrete very little glutamate into the extracellular space (Figure 1). By contrast, activated microglia produce excessive amounts of glutamate as a result of upregulation of glutaminase, but not glutamate dehydrogenase. Subsequently, activated microglia release massive amounts of glutamate via gap-junction hemichannels. Inflammatory cytokines such as TNF-α and IFN-γ enhance not only glutaminase expression level but also cell-surface localization of hemichannels in microglia (Eugenin et al., 2001; Takeuchi et al., 2006). These two phenomena may act synergistically to release excess glutamate, leading to excitotoxic neuronal damage (Figure 1). Moreover, the extracellular glutamine level is critical for microglial glutamate production (Takeuchi et al., 2006). In the CNS, glutamine from astrocytes is essential for glutamate production in neurons (Tsacopoulos and Magistretti, 1996), suggesting that it also plays an important role in microglial glutamate production.

Bottom Line: The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects.We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface.Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University Nagoya, Japan.

ABSTRACT
Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g., minocycline) have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus