Gap Junctions and the Connexin Protein Family

Gap junctions (Gj) form conduits between adjacent cells that are composed of connexin (Cx) protein subunits and allow direct intercellular communication. To date, the connexin gene family comprises 20 members in the mouse and 21 members in the human genome, 19 of which can be grouped as sequence-orthologous pairs. The structure of connexin genes is relatively simple. An untranslated exon 1 is separated by an intron of different length from exon 2, containing the uninterrupted coding region and the 3'-untranslated region (3'-UTR). However, in some connexin genes, the untranslated regions and the reading frame are spliced. Among the known "cardiovascular" connexins, Cx37 and Cx40 were demonstrated to be functionally expressed in mouse and human endothelial cells and Cx40, Cx43 as well as Cx45 in cardiomyocytes of both species. Functional properties, like permeabilities, charge selectivity and unitary conductivity were investigated after directed expression of these connexins in cultured cell lines or paired Xenopus oocytes. Targeted deletion of their coding sequence in the mouse genome allowed study of the biological relevance of Cx37, Cx40, Cx43 and Cx45 with regard to cardiovascular morphology and function. After ablation of Cx37 or Cx40, mice were viable and could be used to study defects in the adult cardiovascular system but loss of Cx43 or Cx45 led to neonatal or embryonic lethality, respectively. Conditional and cell-type specific deletion of both connexins in the heart or blood vessels can help to overcome this obstacle. As yet only little is known about mutations in the human genes for Cx37, Cx40, Cx43 and Cx45. Thus, a profound comparison between human and mouse phenotypes is not yet possible.