GAP JUNCTIONS CONTAIN CHANNELS that allow the passage of ions and small molecules between adjacent cells. This intercellular communication has been implicated in the coordination of cellular responses to intracellular signaling molecules. Calcium and inositol phosphates are among the second messengers that can pass through gap junction channels (15). Stimulation of a cell can elicit a rise in calcium that is then propagated as a “wave” to many surrounding cells. Studies of tracheal epithelial cells have suggested that these calcium waves are mediated by gap junction-mediated intercellular passage of inositol trisphosphate (3, 16, 17). Interventions such as the delivery of antibodies directed against gap junction proteins (connexins) have strongly supported the role of gap junctions in this process (2). The current paper by Boitano and Evans (4) provides further evidence toward this conclusion. Propagated calcium waves have been extensively investigated in many different cell types (5, 7; reviewed in Ref. 18). Although in some cases intercellular calcium waves are mediated by gap junctions, in others they appear to be mediated by passage of extracellular messengers (eg, interaction of ATP released from a stimulated cell with P2 purinergic receptors on adjacent cells leads to increased intracellular calcium and further ATP secretion by the adjacent cells, producing a propagated ATP-induced calcium wave)(13). The most interesting aspect of the Boitano and Evans (4) paper is their use of short peptides corresponding to sequences within the extracellular loops of connexins as inhibitors of intercellular communication. This approach is based on our current understanding of connexin structure and topology. Hydropathy plots originally suggested that a connexin contained fourtransmembrane-spanning regions and two short extracellular loops (14). The disposition of the first and second extracellular regions was confirmed by the production of anti-peptide antibodies that were used for immunolocalization of the corresponding epitopes on split gap junctions (10, 21). To form complete gap junction channels, the extracellular domains of hemichannels contributed by two adjacent cells must “dock” with each other. Therefore, it was hypothesized that reagents that interfered with the interactions of these extracellular domains might impair cell-to-cell communication. Unfortunately, although the antibodies against the extracellular loop amino acid sequences were useful for immunocytochemical studies, they were of limited utility as reagents for blocking cell-tocell communication (12). An alternative approach was developed with the hypothesis that small peptides corresponding to these extracellular connexin domains might impair the interactions of the extracellular loops by binding to their recognition sites in a hemichannel (Fig. 1). Dahl et al.(8) examined the effectiveness of peptides as inhibitors of cell-cell channel formation produced by connexin (Cx) 32 expressed in paired Xenopus oocytes. They found that peptides representing the two extracellular loops of Cx32 as well as five smaller peptides corresponding to subsets of these peptides (Table 1) were quite effective. A number of subsequent papers have used a similar strategy, with the intent of blocking the function of endogenous connexins in various systems. These studies have identified peptides that are effective inhibitors of intercellular communication or of various physiological processes likely mediated by gap junction channels.(The peptides used by the different authors and the connexins of origin are listed in Table 1.) Because of differences in the experimental systems studied, several …