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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

The composition of gap junctions and hemichannels. Each colored column (orange, blue, green, or purple) represents a different connexin isoform. Hemichannels may be homomeric (composed of one connexin isoform) or heteromeric (composed of more than one connexin isoform). Gap-junction channels may be homotypic (formed by identical hemichannels) or heterotypic (formed by different hemichannels).
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Figure 2: The composition of gap junctions and hemichannels. Each colored column (orange, blue, green, or purple) represents a different connexin isoform. Hemichannels may be homomeric (composed of one connexin isoform) or heteromeric (composed of more than one connexin isoform). Gap-junction channels may be homotypic (formed by identical hemichannels) or heterotypic (formed by different hemichannels).

Mentions: Gap junctions contribute to formation of intercellular channels that directly connect the cytoplasmic compartments of neighboring cells (Yeager and Harris, 2007). These channels pass various small molecules (~1000 Da) and ions, although the charges and shapes of these molecules may affect the rate of transfer through gap junctions (Goldberg et al., 2004). Each gap junction is composed of a pair of hemichannels docked in a head-to-head configuration. Hemichannels are organized as hexagonal cylinders with central pores, and each hemichannel consists of a hexameric cluster of protein subunits called connexins (in vertebrates) or innexins (in invertebrates). Connexins are encoded by a conserved family of genes with at least 21 members in mammals. There are 21 connexin genes in the human genome and 20 connexin genes in the mouse genome; 19 of these proteins have orthologs in both humans and mice (Willecke et al., 2002; Laird, 2006). The connexin isoforms structurally interact in multiple ways. Homomeric hemichannels consist of a single connexin isoform, whereas heteromeric hemichannels contain two or more different connexin isoforms. Likewise, a homotypic gap junction channel is composed of two identical hemichannels, whereas a heterotypic gap junction channel contains two different hemichannels. Thus, the compositions of gap junctions can be classified into four types: homomeric and homotypic; heteromeric and homotypic; homomeric and heterotypic; and heteromeric and heterotypic (Figure 2). This heterogeneity of connexin configurations confers complexity to the gap junction/hemichannel system.


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

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

The composition of gap junctions and hemichannels. Each colored column (orange, blue, green, or purple) represents a different connexin isoform. Hemichannels may be homomeric (composed of one connexin isoform) or heteromeric (composed of more than one connexin isoform). Gap-junction channels may be homotypic (formed by identical hemichannels) or heterotypic (formed by different hemichannels).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: The composition of gap junctions and hemichannels. Each colored column (orange, blue, green, or purple) represents a different connexin isoform. Hemichannels may be homomeric (composed of one connexin isoform) or heteromeric (composed of more than one connexin isoform). Gap-junction channels may be homotypic (formed by identical hemichannels) or heterotypic (formed by different hemichannels).
Mentions: Gap junctions contribute to formation of intercellular channels that directly connect the cytoplasmic compartments of neighboring cells (Yeager and Harris, 2007). These channels pass various small molecules (~1000 Da) and ions, although the charges and shapes of these molecules may affect the rate of transfer through gap junctions (Goldberg et al., 2004). Each gap junction is composed of a pair of hemichannels docked in a head-to-head configuration. Hemichannels are organized as hexagonal cylinders with central pores, and each hemichannel consists of a hexameric cluster of protein subunits called connexins (in vertebrates) or innexins (in invertebrates). Connexins are encoded by a conserved family of genes with at least 21 members in mammals. There are 21 connexin genes in the human genome and 20 connexin genes in the mouse genome; 19 of these proteins have orthologs in both humans and mice (Willecke et al., 2002; Laird, 2006). The connexin isoforms structurally interact in multiple ways. Homomeric hemichannels consist of a single connexin isoform, whereas heteromeric hemichannels contain two or more different connexin isoforms. Likewise, a homotypic gap junction channel is composed of two identical hemichannels, whereas a heterotypic gap junction channel contains two different hemichannels. Thus, the compositions of gap junctions can be classified into four types: homomeric and homotypic; heteromeric and homotypic; homomeric and heterotypic; and heteromeric and heterotypic (Figure 2). This heterogeneity of connexin configurations confers complexity to the gap junction/hemichannel system.

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