Recent advances in connexin gap junction biology

Abstract

Connexins are assembled into dodecamer intercellular channels, a collection of which is termed a gap junction, and their canonical function allowing direct exchange of ions and metabolites has been unequivocally established. When initially assembled into undocked cell surface connexin hemichannels, healthy cells may also engage in cell signaling via a regulated small-molecule release. Recent advances in the field have led to an expanded view of the functional roles of intercellular channels and hemichannels in both physiology and pathology. As more of the 21-member human connexin family is intensely interrogated, mounting evidence points to the biological uniqueness of each member, and no longer can we confidently refer to all connexins engaging in the same cellular processes. Innovations in high-resolution cryo-electron microscopy have revealed important insights into the structure of functionally important domains of both hemichannels and channels. These and other studies have established a foundation of knowledge that should allow inhibitory smart drug design for situations where enhanced intercellular or hemichannel activity is at the root of a connexin-linked disease. Assessment of the connexin interactome, which varies widely for each connexin subtype, continues to provide regulatory insights into the assembly and function of connexins that exhibit a short half-life. As the most intensely studied, Cx43 is found in about 50% of all human cell types and is extensively regulated by multiple inhibitory and enhancing phosphorylation events that have direct implications on tissue function and outcomes of disease, including cancer. Here, we briefly discuss these advances and give our thoughts on where the field is headed.

Keywords: channel; connexin; gap junctions; hemichannel.

Figure 1.. Assembly of Cx43 during its life cycle.

Cx43 is produced in the endoplasmic reticulum (ER) and is exported to the Golgi apparatus as a monomer. In the Golgi, Cx43 oligomerizes into hexamers and is exported to the plasma membrane, where it can exist as a closed (red channel) or open (green) hemichannel that can allow the regulated passage of specific small molecules (denoted by stars and ovals). Hemichannels from adjoining cells dock and form a head-to-head dodecameric structure (gap junction channel) to permit the regulated intercellular passage of small molecules and metabolites.

Figure 2.. Map of the C-terminal tail of Cx43 with phosphorylation sites having known regulatory functions indicated.

The specified protein kinases and the Cx43 residues they are known to be phosphorylated by are denoted by distinct colors. The site at S365 (purple) is phosphorylated by an unknown kinase that is influenced by protein kinase A activity (i.e., the effect is likely indirect). CAMKII has also been reported to phosphorylate several additional residues in vitro.