Atrial gap junction remodeling: looking for lost gaps and orphaned connexins in three dimensions.

Gap junction channels are composed of members of a multi-gene family of proteins called connexins. These proteins are named by the abbreviation Cx followed by the molecular weight of the specific protein. Mammalian cardiac myocytes express Cx43, Cx45, and Cx40, the former being the major cardiac gap junction protein, which is expressed in atrial and ventricular myocytes as well as in selected regions of the atrioventricular conduction system [1,2]. Individual gap junction channels (also called connexons) formed by multiple connexin molecules exhibit distinct unitary conductance, pH and voltage dependence, and permeability to ions and small molecules as well as fluorescent dyes [3]. Regulation of the extent to which cardiac myocytes are electrically coupled by gap junction channels is complex and still not well understood [4,5]. In general, it appears that cells can rapidly (within minutes) change the number of functional channels at the cell surface through multiple mechanisms involving mobilization of intracellular connexin molecules to junctional plaques, internalization of junctional channels, changes in channel open probability and, potentially, changes in rates of connexin synthesis and degradation. Phosphorylation of multiple serine and tyrosine residues in the intracellular C-terminal domains has been shown to be important in Cx43 and Cx45 assembly into gap junction channels and in changes in channel function, intracellular translocation, and degradation [6]. Indeed, Cx43 can be phosphorylated on specific serine residues by mitogenactivated protein (MAP) kinases, protein kinases C (PKC) and