title: Glial hemichannels and their involvement in aging and neurodegenerative diseases.
abstract: During the last two decades, it became increasingly evident that glial cells accomplish a more important role in brain function than previously thought. Glial cells express pannexins and connexins, which are member subunits of two protein families that form membrane channels termed hemichannels. These channels communicate intra- and extracellular compartments and allow the release of autocrine/paracrine signaling molecules [e.g., adenosine triphosphate (ATP), glutamate, nicotinamide adenine dinucleotide, and prostaglandin E2] to the extracellular milieu, as well as the uptake of small molecules (e.g., glucose). An increasing body of evidence has situated glial hemichannels as potential regulators of the beginning and maintenance of homeostatic imbalances observed in diverse brain diseases. Here, we review and discuss the current evidence about the possible role of glial hemichannels on neurodegenerative diseases. A subthreshold pathological threatening condition leads to microglial activation, which keeps active defense and restores the normal function of the central nervous system. However, if the stimulus is deleterious, microglial cells and the endothelium become overactivated, both releasing bioactive molecules (e.g., glutamate, cytokines, prostaglandins, and ATP), which increase the activity of glial hemichannels, reducing the astroglial neuroprotective functions, and further reducing neuronal viability. Because ATP and glutamate are released via glial hemichannels in neurodegenerative conditions, it is expected that they contribute to neurotoxicity. More importantly, toxic molecules released via glial hemichannels could increase the Ca2+ entry in neurons also via neuronal hemichannels, leading to neuronal death. Therefore, blockade of hemichannels expressed by glial cells and/or neurons during neuroinflammation might prevent neurodegeneration.
authors.affiliation: Facultad de Medicina, Departamento de Neurología, Pontificia Universidad Católica de Chile, Santiago, Chile. jaorella@uc.cl
authors.forename: Juan A
authors.initials: JA
authors.lastname: Orellana
authors.forename: Rommy
authors.initials: R
authors.lastname: von Bernhardi
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism* / Q000494:pharmacology; D002490:Central Nervous System / Q000502:physiology; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017630:Connexins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D007473:Ion Channels / Q000502:physiology*; D009243:NAD / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002186:Cannabinoids; D018031:Connexin 43; D017630:Connexins; D053583:Interleukin-1beta; D007473:Ion Channels; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D015232:Dinoprostone; D002118:Calcium