The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions

Abstract

Ischemic stroke is a multi-factorial cerebrovascular disease with high worldwide morbidity and mortality. In the past few years, multiple studies have revealed the underlying mechanism of ischemia/reperfusion injury, including calcium overload, amino acid toxicity, oxidative stress, and inflammation. Connexin 43 (Cx43), the predominant connexin protein in astrocytes, has been recently proven to display non-substitutable roles in the pathology of ischemic stroke development and progression through forming gap junctions and hemichannels. Under normal conditions, astrocytic Cx43 could be found in hemichannels or in the coupling with other hemichannels on astrocytes, neurons, or oligodendrocytes to form the neuro-glial syncytium, which is involved in metabolites exchange between communicated cells, thus maintaining the homeostasis of the CNS environment. In ischemic stroke, the phosphorylation of Cx43 might cause the degradation of gap junctions and the opening of hemichannels, contributing to the release of inflammatory mediators. However, the remaining gap junctions could facilitate the exchange of protective and harmful metabolites between healthy and injured cells, protecting the injured cells to some extent or damaging the healthy cells depending on the balance of the exchange of protective and harmful metabolites. In this study, we review the changes in astrocytic Cx43 expression and distribution as well as the influence of these changes on the function of astrocytes and other cells in the CNS, providing new insight into the pathology of ischemic stroke injury; we also discuss the potential of astrocytic Cx43 as a target for the treatment of ischemic stroke.

Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury

“…It has been described that, early after an ischemic insult (1–30 min), Cx43 gap junctions are phosphorylated by several kinases, like MAPK, PKC, pp60Src, and casein kinase 1δ, which triggers internalization of Cx43 hexamers. The remaining Cx43 hemichannels are dephosphorylated in a subsequent stage (after 60 min), increasing their opening probability and allowing harmful molecules into the extracellular space (ECS), like ATP and glutamate [ 84 ]. Leptin was found to suppress Cx43 rise after I/R reducing brain damage in a mouse model of MCAO, and it also blocked Cx43 hemichannels in cultured U87 cells [ 85 ].…”

“…At higher exposure times Gap19 slightly inhibits gap junctions. Suppression of Cx43 by Gap19 showed beneficial effects in MCAO mouse models [ 84 ].…”

The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury

“…Cx43 is the primary component protein of connexin channels in brain tissue, and its enhanced expression can accelerate intercellular signal transduction, aggravating damage after injury. Studies have shown that hypoxia and inflammation synergistically accelerate the activity of Cx43 hemichannels under ischemic conditions (Faigle et al, 2008), leading to the loss of astrocytes and neuronal death (Liang et al, 2020). One study showed that 1 hour after TBI, the expression of phosphorylated Cx43 in the ipsilateral hippocampus was significantly induced and remained at a high level until 24 hours after injury.…”

First Responders to Hyperosmotic Stress in Murine Astrocytes: Connexin 43 Gap Junctions Are Subject to an Immediate Ultrastructural Reorganization

“…Although Connexin (Cx) 26, Cx30, and Cx43 were shown to play a role in brain homeostasis, Cx43 is considered the main gap junction protein in astrocytes. A number of in vivo and in vitro studies, using pharmacological gap junction inhibition or the deletion or overexpression of Cx43, confirmed the relevance of Cx43 for astrocytic well-being [ 7 , 8 , 9 ].…”