Connexins (Cxs) are encoded by a large gene family predicted to include at least 20 isoforms in humans. Most mammalian Cx genes consist of two exons. The first consists of untranslated sequence, and the second contains the entire coding sequence. Exceptionally, Cx36 and Cx45 contain 3 exons and 2 introns and the third exon contains the coding sequence (Belluardo et al. 1999 ; Jacob and Beyer 2001). Connexins have been divided in two major subgroups, alpha and beta, according to their amino acid sequence similarity (see Bruzzone et al., 2001; Willecke et al., 2002). Alternative names and additional subgroups have been suggested as well. Cx are synthesized by ribosomes in the endoplasmic reticulum (ER) membrane. All Cx proteins contain four trans-membrane domains (TM1 to TM4), two extracellular loops (E1 and E2) and one cytoplasmic loop. The amino- and carboxyl termini are located in the cytosol (reviewed in Segretain and Falk, 2004). After targeting to the ER, connexins are checked by a quality control system to prevent misfolded forms from progressing through the secretory pathway. Aberrant proteins are removed by endoplasmic-reticulum-associated degradation (ERAD).