Fig. 1.

Structural organization of a connexin (Cx) protein, a connexon hemichannel, and a gap junction. One connexon or hemi-channel is formed by the association of six connexin (Cx) proteins. Two hexameric connexons between two adjoining cells dock to form a gap junction channel. Topologically, one Cx is composed of four transmembrane domains (M1 to M4), two extracellular loops (E1 and E2), one intracellular loop (IL), and intracellular amino (NH₂) and carboxy (COOH)-termini. E1 and E2 have three cysteine residues (C) that form disulfide bonds with adjoining Cx proteins, allowing the docking of two connexons. The Cx-mimetic blocking peptides Gap26 and Gap27 specifically target E1 and E2, respectively. The C-terminal is subjected to a variety of post-translational modifications, including phosphorylation at the S255, S279, and S282 sites by the mitogen-activated protein kinases (MAPK)