Gap junction synthesis and degradation as therapeutic targets

The synthesis and the degradation of gap junctions involve multiple steps that may provide targets for the modulation of intercellular communication. Many studies using cultured cells have examined the effects of inhibitors of protein synthesis. trafficking, or degradition upon connexins. Similarly, activators or inhibitors of various protein kinases have been shown to affect connexin assembly or proteolysis. These studies have helped to elucidate the connexin life-cycle. But, because of their lack of specificity for gap junction proteins, these agents would be expected to have limited therapeutic utility and to produce several deleterious side effects. However, more selective agents are being developed based on specific features of the connexin sequences, Molecular genetic approaches have been used to introduce wild-type connexins to increase intercellular communication in otherwise poorly coupled cells. Decreased intercellular communication may be obtained by application of peptides that mimic the extracellular loops and may prevent docking of hemi-channels. Alternatively, introducing mutant connexins that interfere with the oligomerization/export of endogenous connexins or with channel function by formation of non-functional heteromeric hemi-channels can also reduce intercellular communication.