ENDOGENOUS AND EXOGENOUS MODULATION OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION - TOXICOLOGICAL AND PHARMACOLOGICAL IMPLICATIONS

During the evolution of single-celled organisms to multi-cellular meta zoans, a family of highly conserved genes coding for proteins (connexi ns), which as hexameric units (connexons), has evolved to form interce llular channels (gap junctions). These gap junctions allow ions and sm all molecular weight molecules to flow between coupled cells, thereby facilitating synchronization of electrotonic or metabolic cooperation. Control of cell proliferation, cell differentiation and adaptive resp onses of differentiated cells have been speculated to be biological ro les of gap junctions. The regulation of these gap junctions can occur at the transcriptional, translational and posttranslational levels. Tr ansient downregulation by endogenous or exogenous chemicals can bring about adaptive or maladaptive consequences depending on circumstances. Stable abnormal regulation of gap junction function has been associat ed with the activation of several oncogenes. Several tumor suppressor genes have also been associated with the up-regulation of gap junction function. Since gap junctions exist in all organs of the multi-cellul ar organisms, the dysfunction of these gap junctions by various toxic chemicals which have cell type/tissue/organ specificity could bring ab out very distinct clinical consequences, such as embryo lethality or t eratogenesis, reproductive dysfunction in the gonads, neurotoxicity of the CNS system, hyperplasia of the skin, and tumor promotion of initi ated tissue. understanding how many non-mutagenic chemicals might alte r normal gap junction function should form the basis of ''epigenetic'' toxicology. On the other hand, restoring normal gap junction function to cells which have dysfunctional intercellular communication could b e the basis for a new approach for therapeutic pharmaceuticals.