Fig. 4. Cx43 dysfunction contributes to depression through peripheral mechanisms.

(1) ERS in hepatocytes spreads through Cx43 GJCs and promotes insulin resistance. (2) Insulin resistance causes Cx43 GJC dysfunction by increasing the level of H₂O₂ in vascular smooth muscle cells. (3) TSH promotes TH production by increasing the synthesis of Cx43 and inducing the opening of Cx43 GJCs in thyrocytes. (4) Excessive CORT produced by adrenocortical cells causes Cx43 GJC dysfunction of astrocytes in the brain. (5) Under conditions of stress, activated microglia releases inflammatory factors, promoting Cx43 HC opening and Cx43 GJC dysfuntion of astrocytes. (6) Opened HCs further contribute to the activation and spread of the inflammasome pathway. (7) Insulin resistance can promote neuroinflammation and affect the brain function. CORT corticosterone, ERS endoplasmic reticulum stress, GJCs gap junction channels, HC hemichannel, TH thyroid hormone, TSH thyroid stimulating hormone.