General Cell Biology of Connexins
Similar to other transmembrane proteins, connexin translation occurs on the ribosomes attached to the endoplasmic reticulum (ER), followed by co-translational release of the protein in the lumen of ER. During the transport of connexins from ER to Golgi network, they are folded into the three-dimensional structure, followed by their oligomerization into hexameric hemichannels called connexons. Each connexon subunits can be either homomeric (made of similar connexins) or heteromeric (made of different connexins). The possibility of forming the heteromeric connexin channels is significant, as many cells express more than one type of connexin protein. Hence, more the expression of different connexins in a cell, the possibility of forming various permutation combinations of connexin channels increases significantly. Moreover, channels formed of heteromeric connexons have different properties from those of homomeric channels of the constituent connexins, thereby allowing for critical regulation of the permeability and conductance of gap junctions. However, it is regarded that there exists some selective compatibility between various connexins to form heterotypic channels, and this compatibility has been attributed to the N-terminal and C-terminal domains of each connexin. Furthermore, the transport of connexon hemichannels involves their packaging into vesicles, and then these vesicles deliver the connexon hemichannels to the plasma membrane. The transport of these vesicles to the plasma membrane has been demonstrated to be both microtubule and actin mediated. The insertion of connexon hemichannels to the plasma membrane is regarded to be random. However, some studies have shown that microtubules target the connexon hemichannels to a specific domains or regions of plasma membrane, which are rich in adherens junction proteins. The inserted connexon hemichannels interact with the apposing connexion hemichannels of adjacent cell, thus allowing the formation of complete intercellular gap junction channel. The interaction between the apposing connexon hemichannels is mediated by the external loop domains. The individual channels aggregate in the membrane to form plaques and hence are known as gap junction plaques. However, under certain conditions, the inserted connexon hemichannels remain uncoupled, thus connecting the intracellular milieu directly to the extracellular. The existence of these hemichannels has been well established and is known to play important roles in cell physiology.