Connexin 43 Phosphorylation: Implications in Multiple Diseases

Abstract

Connexin 43 (Cx43) is most widely distributed in mammals, especially in the cardiovascular and nervous systems. Its phosphorylation state has been found to be regulated by the action of more than ten kinases and phosphatases, including mitogen-activated protein kinase/extracellular signaling and regulating kinase signaling. In addition, the phosphorylation status of different phosphorylation sites affects its own synthesis and assembly and the function of the gap junctions (GJs) to varying degrees. The phosphorylation of Cx43 can affect the permeability, electrical conductivity, and gating properties of GJs, thereby having various effects on intercellular communication and affecting physiological or pathological processes in vitro and in vivo. Therefore, clarifying the relationship between Cx43 phosphorylation and specific disease processes will help us better understand the disease. Based on the above clinical and preclinical findings, we present in this review the functional significance of Cx43 phosphorylation in multiple diseases and discuss the potential of Cx43 as a drug target in Cx43-related disease pathophysiology, with an emphasis on the importance of connexin 43 as an emerging therapeutic target in cardiac and neuroprotection.

Keywords: connexin 43; intercellular communication; phosphorylation; the cardiovascular system; the nervous system.

Figure 1

Changes in Cx43 phosphorylation in major diseases of the cardiovascular system and the nervous system and its influence on Cx43 HCs and Cx43 GJIC. Cx43, Connexin 43; HC, hemichannel; GJIC, gap junction intercellular communication; ↑, Increase; ↓, Decrease.

Figure 2

Schematic representation of Cx43 expression and phosphorylation of astrocytes in depression. (1) CORT reduced the synthesis of Cx43 and the distribution of Cx43 in the membrane in astrocytes. (2) Cx43 was degraded by a proteasome. (3) CORT reduced the distribution of Cx43 in the membrane and in the meantime increased the phosphorylation of Cx43 at Ser368 in the prefrontal cortical astrocytes and hippocampal astrocytes, thereby inhibiting the communication mediated by gap junctions.

Figure 3

(1) In Aβ_1–42-stimulated astrocytes, phosphorylation of Cx43 Ser368 residues is enhanced, resulting in a surge in hemichannel activity and ATP release. (2) A_2AR directly regulates hemichannel activity and inhibits the upregulation and phosphorylation of Cx43 in Aβ_1–42-exposed astrocytes. (3) Cx43 expression is increased in AD patients. (4) In rotenone-treated cultured astrocytes, Cx43 protein levels and phosphorylation levels were enhanced, and phosphorylated Cx43 led to gap junction cell-to-cell communication dysfunction. (5) In epilepsy, phosphorylation of Cx43 results in the release of K+ and glutamate, which increases connection conductance.