ellular communication is essential for any metazoan to perform routine activities, and throughout evolution, various strategies for cellular interactions have developed. The immune system is a good example of this diversity, exhibiting virtually all types of cell-cell interactions described so far, and allowing homotypic and heterotypic communication among lymphoid and microenvironmental cells. Nonetheless, scarce attention has been given to interactions mediated by gap junctions, which allow direct electrotonic coupling and passage of small molecules between adjacent cells [1][2][3] .
What is a gap junction?
The first evidence of gap-junction-mediated cell-cell communication appeared in the 1950s, when direct passage of electrical signals was detected by standard electrophysiological techniques in crayfish synapses 4 . Not until 1967 were these junctions definitively demonstrated by electron microscopy, using the extracellular tracer lanthanum nitrate. This molecule was visualized in 2-4 nm wide extracellular 'gaps' between adjacent cell membranes, thus distinguishing them from tight junctions, and giving rise to the name gap junctions 5 .
Gap junctions are macromolecular structures forming channels that directly connect adjacent cells, allowing passage of molecules up to 1 kDa in size between mammalian cells 1-3 . Thus, ions, second messengers and other small molecules can be exchanged between cells. Gap junction channels can be regulated by several agents, including voltage, intracellular calcium and pH, adhesion proteins, extracellular matrix and hormones [1][2][3] .
Each junctional channel comprises two sets of six-protein subunits assembled in the plasma membrane forming a hemichannel or connexon (Fig. 1), which is joined to its adjacent counterpart by noncovalent interactions across the extracellular space 1-3 . The family of proteins that form gap junctions are named connexins (Cxs), of which 13 members have been cloned and sequenced from mammalian tissues; several homologues have also been defined in nonmammalian vertebrate species. Cxs can be classified based on their molecular weights deduced from corresponding cDNA sequences. Members of the Cx family have the same basic structure: cytosolic N-and C-termini, four transmembrane domains, two extracellular loops and one cytoplasmic loop (Fig. 1c).
Recently, Cx isoforms have been found to convey specific properties to the gap junction channels, including differential molecular weight permeability and ionic selectivity [6][7][8] . Interestingly, a given Cx can form a functional channel only with certain isoforms 9,10 .