Abstract
In the central nervous system (CNS), astrocytes form networks interconnected by gap junctions made from connexins of the subtypes Cx30 and Cx43. When unopposed by an adjoining hemichannel, astrocytic connexins can act as hemichannels to control the release of small molecules such as ATP and glutamate into the extracellular space. Accruing evidence indicates that astrocytic connexins are crucial for the coordination and maintenance of physiologic CNS activity. Here we provide an update on the role of astrocytic connexins in neurodegenerative disorders, glioma, and ischemia. In addition, we address the regulation of Cx43 in chronic pain.
Highlights
As the most abundant cells in the central nervous system, astrocytes are critical for synaptic transmission and homeostasis maintenance
Unpaired connexins can act as hemichannels, which are responsible for the release of gliotransmitters, including ATP, glutamate, nicotinamide adenine dinucleotide (NAD), and D-serine to the extracellular milieu (Saez et al, 2003; Retamal et al, 2014)
Astrocytes modulate extrasynaptic or synaptic milieu to further enhance or dampen electrochemical signaling propagating in neurons
Summary
As the most abundant cells in the central nervous system, astrocytes are critical for synaptic transmission and homeostasis maintenance. The activated hemichannels increase the release of ATP and glutamate from astrocytes around the amyloid plaques, leading to overload of neuronal Ca2+, synaptic depression (Pascual, 2005), and final neuronal damage (Yi et al, 2016). In APP/PS1 mice, a specific deletion of astroglial Cx43 could significantly reduce astrogliosis and increase synapse numbers, though it had no effects on amyloid plaque formation or inflammatory response (Ren et al, 2018) These results indicate that Cx43 could be a novel therapeutic target for AD. Cx43 expression was found upregulated in patients with amyotrophic lateral sclerosis (ALS) or related models (Almad et al, 2016) This upregulated Cx43 expression led to elevated hemichannel activity, enhanced gap junction coupling and increased intracellular Ca2+ concentration, which contributed to motor neuron toxicity. This poor prognosis is mainly caused by the resistance to the chemotherapeutic alkylating agents such as temozolomide (TMZ), and the invasive nature of the tumor cells (Sin et al, 2012, 2016; Wang et al, 2018)
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