Figure 2.

The phosphorylation of astrocytic Cx43 C-terminal and its influence on astrocytes and neurons after ischemic stroke. ① At the early stage of ischemic stroke, astrocytic membrane Cx43, which is involved in the formation of gap junction channels and hemichannels, is phosphorylated at the C-terminal (predominantly from 1 to 30 min) via several protein kinases including protein kinase C, MAPK, pp60Src kinase, and casein kinase 1δ. This process leads to the internalization of membrane Cx43 to the cytoplasm and the degradation of gap junctions. ② At the later stage of ischemic stroke, the remaining astrocytic membrane Cx43 is dephosphorylated (predominantly after 60 min), increasing the permeability of hemichannels. ③ Thus, resulting in the release of ATP, glutamate, and nicotinamide adenine dinucleotide from the cytoplasm of injured astrocytes or injured neurons to the extracellular space, initiating or enhancing neuroinflammation through the remaining gap junctions. ④ In coupled astrocytes, healthy astrocytes could transfer essential ions and metabolites (including Na⁺, K⁺, glutamine, antioxidants, and glucose) to injured astrocytes by Cx43/Cx43 gap junction channels or injured neurons by Cx43/Cx36 gap junction channels and protect the injured astrocytes. In turn, harmful ions and metabolites (including Ca²⁺, ATP, glutamate, NO, and ROS) might also be transferred from injured astrocytes or injured neurons to healthy astrocytes, thus spreading the death wave.