Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation

Anastasia F. Thévenin, Tia J. Kowal, John T. Fong, Rachael M. Kells, Charles G. Fisher, Matthias M. Falk


Gap junctions (GJs) are the only known cellular structures that allow a direct cell-to-cell transfer of signaling molecules by forming densely packed arrays or “plaques” of hydrophilic channels that bridge the apposing membranes of neighboring cells. The crucial role of GJ-mediated intercellular communication (GJIC) for all aspects of multicellular life, including coordination of development, tissue function, and cell homeostasis, has been well documented. Assembly and degradation of these membrane channels is a complex process that includes biosynthesis of the connexin (Cx) subunit proteins (innexins in invertebrates) on endoplasmic reticulum (ER) membranes, oligomerization of compatible subunits into hexameric hemichannels (connexons), delivery of the connexons to the plasma membrane (PM), head-on docking of compatible connexons in the extracellular space at distinct locations, arrangement of channels into dynamic spatially and temporally organized GJ channel plaques, as well as internalization of GJs into the cytoplasm followed by their degradation. Clearly, precise modulation of GJIC, biosynthesis, and degradation are crucial for accurate function, and much research currently addresses how these fundamental processes are regulated. Here, we review posttranslational protein modifications (e.g., phosphorylation and ubiquitination) and the binding of protein partners (e.g., the scaffolding protein ZO-1) known to regulate GJ biosynthesis, internalization, and degradation. We also look closely at the atomic resolution structure of a GJ channel, since the structure harbors vital cues relevant to GJ biosynthesis and turnover.


  • This review provides only a sampling of the literature that is available on this topic, and we apologize to authors whose original works have not been cited.

  • Work in the authors' laboratory is supported by funds from the National Institutes of Health (National Institue of General Medical Sciences Grant GM-55725) to M. M. Falk.

  • No conflicts of interest, financial or otherwise, are declared by the author(s).

  • Author contributions: A.F.T., R.M.K., C.G.F., and M.M.F. prepared figures; A.F.T., T.J.K., J.T.F., R.M.K., C.G.F., and M.M.F. drafted manuscript; A.F.T., T.J.K., J.T.F., R.M.K., C.G.F., and M.M.F. edited and revised manuscript; M.M.F. approved final version of manuscript.

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