Cx43 and Cx45, as examples of connexin family members, typically thread through the membrane four times, with the AT, CT and CL exposed to the cytoplasm. Connexin arrangement in the membrane also yields two extracellular loops designated EL-1 and EL-2. Six connexins oligomerize into a connexon or hemichannel that docks in homotypic, heterotypic and combined heterotypic/heteromeric arrangements. In total, as many as 14 different connexon arrangements can form when two members of the connexin family intermix.

Protein kinases known to phosphorylate Cx43 are shown along the top of a diagrammatically represented gap-junction plaque. A number of scaffolding proteins and proteins of unknown function that have been shown to bind directly or indirectly to Cx43 are shown along the bottom of the gap-junction plaque. It is important to note that it is not necessarily expected that all proteins shown here bind to Cx43 while it is a resident of the gap-junction plaque. MAP kinase, mitogen-activated protein kinase; CIP85, Cx43-interacting protein of 85 kDa.

Schematic diagram of Cx26 depicting a number of mutations associated with deafness (purple balls) and mutations associated with both deafness and skin diseases (orange balls).

Gap-junction channels can be permeable to small molecules (A), small molecules with elongated shapes (B) or combinations of both molecular shapes (C). It is also important to note that the charge of the trans-junctional molecule also governs permeability characteristics. Gap junctions are typically not permeable to molecules exceeding 1 kDa (purple).

Connexins typically co-translationally insert into the ER. If properly folded, it is expected that connexins are spared from ERAD, whereas in other cases they may be targeted for ERAD. For at least some members of the connexin family, complete oligomerization is delayed until the connexin passes through the intermediate compartment and reaches the distal elements of the Golgi apparatus, namely the TGN (trans-Golgi network). Pleiomorphic vesicles and transport intermediates are thought to deliver closed connexons to the cell surface, a process that is facilitated by microtubules. Connexons may function as hemichannels and exchange small molecules with the extracellular environment or laterally diffuse in a closed state to sites of cell–cell apposition and dock with connexons from an opposing cell. In conjunction with cadherin-based cell adhesion, gap-junction channels cluster into plaques, open and exchange secondary messengers. New gap-junction channels are recruited to the margins of gap-junction plaques and older channels are found in the centre of the plaques. Several connexin-binding proteins have been identified, and it is likely that one or more of these binding proteins regulate plaque formation and stability, possibly by acting as scaffolds to cytoskeletal elements. Gap-junction plaques and fragments of gap-junction plaques are internalized into one of two adjacent cells as a double-membrane structure commonly referred to as an annular junction, but renamed in the present review as connexosomes. Other pathways for connexin internalization may exist where connexons disassemble and enter the cell by classical endocytic pathways. Internalized gap junctions are targeted for degradation in lysosomes, although some evidence suggests a role in proteasomal degradation.

Gap junctions composed of connexins, adherens junctions consisting of cadherins and tight junctions made up of occludins and claudins are often closely arranged in epithelial cells and share common binding proteins that scaffold to actin and microfilaments. Binding-protein-mediated cross-talk allows these three junctional complexes to act as a nexus and be governed by some common regulatory events.

Schematic diagram of Cx43 depicting the locations of 28 mutations (red balls) linked to ODDD.