Analysis of the function and therapeutic strategy of connexin 43 from its subcellular localization

Connexins (Cxs) are a family of transmembrane proteins located in the plasma membrane of human cells, among which connexin 43 (Cx43) is abundantly expressed in various types of human cells. Cx43, encoded by the gap junction protein alpha 1 (GJA1) gene, assembles into a hexameric structure in the Golgi apparatus and translocates to the plasma membrane to form hemichannels (Hcs), which pair with those of the cells in contact with each other and form gap junction intercellular communication (GJIC). The role of Cx43 as a connexin localized at the plasma membrane to perform channel functions is well recognized in previous studies, but recent studies have found that it can also be localized in the nucleus, mitochondria, or present in extracellular vesicles (EVs) and tunneling nanotubes (TNTs). Cx43 in the nucleus is involved in gene transcription regulation, cytoskeleton formation, cell migration and adhesion. Cx43 in mitochondria is involved in mitochondrial respiration-related functions, and Cx43 in extracellular vesicles and tunneling nanotubes is involved in distant cellular information exchange. It is because of the diverse distribution of subcellular localization of Cx43 that it is possible to explore the corresponding functions by analyzing its localization. In this review, we summarize the important roles of Cx43 in disease development from the perspective of subcellular localization, and provide new ideas for Cx43 as a therapeutic target and the search for related pathological mechanisms.