Regulation of connexin biosynthesis, assembly, gap junction formation, and removal

Gap junctions (GJs) are the only known cellular structures that allow a direct transfer of signaling molecules from cell-to-cell by forming hydrophilic channels that bridge the opposing membranes of neighboring cells. The crucial role of GJ-mediated intercellular communication (GJIC) for coordination of development, tissue function, and cell homeostasis is now well documented. In addition, recent findings have fueled the novel concepts that connexins, although redundant, have unique and specific functions, that GJIC may play a significant role in unstable, transient cell-cell contacts, and that GJ hemi-channels by themselves may function in intra-/extracellular signaling. Assembly of these channels is a complicated, highly regulated process that includes biosynthesis of the connexin subunit proteins on endoplasmic reticulum membranes, oligomerization of compatible subunits into hexameric hemi-channels (connexons), delivery of the connexons to the plasma membrane, head-on docking of compatible connexons in the extracellular space at distinct locations, arrangement of channels into dynamic, spatially and temporally organized GJ channel aggregates (so-called plaques), and coordinated removal of channels into the cytoplasm followed by their degradation. Here we review the current knowledge of the processes that lead to GJ biosynthesis and degradation, draw comparisons to other membrane proteins, highlight novel findings, point out contradictory observations, and provide some provocative suggestive solutions.