Trafficking Pathways Leading to the Formation of Gap Junctions

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Abstract
This chapter reports the mechanisms resulting in the assembly of gap junction intercellular communication channels. The connexin channel protein subunits are required to oligomerize into hexameric hemichannels (connexons) that may be homo‐ or heteromeric in composition. Pairing of connexons in contacting cells leads to the formation of a gap junction unit. Subcellular fractionation studies using guinea‐pig liver showed that oligomerization of connexins was complete on entry into Golgi, and that connexons showed heteromeric properties. The low ratio of connexin26 (Cx26; β2) relative to Cx32 (β1) in endomembranes compared to the approximately equal ratios found in plasma membranes and gap junctions suggest that Cx26 takes a non‐classical route to the plasma membrane. Cultured cells, expressing connexin–aequorin chimeras, also provided evidence that Cx26 takes a more rapid non‐classical route to the plasma membrane, because brefeldin A, a drug that disrupts the Golgi, had minimal effects on trafficking of Cx26 to the plasma membrane in contrast to its disruption of Cx32 trafficking. Finally, a cell‐free approach for studying synthesis of connexons provided further evidence that Cx26 showed membrane insertion properties compatible with a more direct intracellular route to gap junctions. The presence of dual gap junction assembly pathways can explain many of the differential properties exhibited by connexins in cells.