Abstract
Although originally considered a structural component of gap junctions, connexin hemichannels (HCs) are now recognized as functional entities capable of influencing metabolic gradients within the CNS, allowing direct communication between the intra- and extracellular milieus. Besides connexins, HCs can also be formed by pannexins, which are not capable of gap junction assembly. Both positive and negative effects have been attributed to HC activity in the context of neurodegenerative diseases. For example, HCs can exert neuroprotective effects by promoting the uptake of neurotoxic molecules, whereas chronic HC opening can disrupt molecular gradients leading to cellular dysfunction and death. The latter scenario has been suggested for multiple neurodegenerative disorders, including Alzheimer’s disease (AD) and more recently, lysosomal storage disorders, which are the focus of this perspective. Currently available evidence suggests a complex role for HCs in neurodegenerative disorders, which sets the stage for future studies to determine whether targeting HC action may improve disease outcomes.
Highlights
CELLULAR NEUROSCIENCEEdited by: Juan Andrés Orellana, Pontificia Universidad Católica de Chile, Chile
Hemichannels (HCs) are composed of six connexin (Cx) subunits that assemble into hexameric pores that traffic to the plasma membrane where they can remain uncoupled or pair with adjacent HCs on neighboring cells to form gap junction channels (Contreras et al, 2003)
HCs are permeable to small hydrophilic molecules, such as ATP, Ca2+, glutamate, glucose, and glutathione, which are critical for CNS homeostasis by maintaining ionic and metabolic gradients and can control autocrine/paracrine signaling (Retamal et al, 2007; Kielian, 2008; Rouach et al, 2008; Sánchez et al, 2009; Schalper et al, 2010; Orellana et al, 2011a; Bennett et al, 2012; Fiori et al, 2014)
Summary
Edited by: Juan Andrés Orellana, Pontificia Universidad Católica de Chile, Chile. HCs can be formed by pannexins, which are not capable of gap junction assembly Both positive and negative effects have been attributed to HC activity in the context of neurodegenerative diseases. HCs can exert neuroprotective effects by promoting the uptake of neurotoxic molecules, whereas chronic HC opening can disrupt molecular gradients leading to cellular dysfunction and death. The latter scenario has been suggested for multiple neurodegenerative disorders, including Alzheimer’s disease (AD) and more recently, lysosomal storage disorders, which are the focus of this perspective.
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