Chapter 3: Homotypic, Heterotypic, and Heteromeric Gap Junction Channels

Abstract

Mammalian gap junction channels are formed when each cell of an adjacent pair contributes six connexins to form an oligomerized hemichannel. Any two hemichannels can form a link through extracellular loops extending from their respective membrane-spanning domains to form an aqueous intercellular pathway. Gap junction channels are therefore composed of 12 subunit proteins. These subunits are referred to as “connexins” and are named according to their predicted molecular weights. The biophysical characteristics of the gap junction family of proteins have been rigorously studied. Historically, however, most electrophysiological studies of connexins have concentrated on elucidating the macroscopic behavior and unitary conductance of homotypic gap junction channels, that is, gap junction channels formed of 12 identical connexin proteins. However, because many cell types express more than one connexin protein, distinct combinations of these intercellular channels among parenchymal cells within a given tissue are, at the very least, theoretically possible. In particular, it is quite conceivable that gap junction channels in a given tissue cell type can also be formed by the union of hemichannels that are each composed of homologous, but different connexin proteins. Recently, evidence has been advanced consistent with the supposition that the expression of more than one connexin type in a single cell results in the mixing of nonidentical connexins (i.e., heteromeric) in a given hemichannel or connexon. As such, this chapter reviews the extant evidence for heteromeric connexins formed of the two most prominent connexins found in vascular wall cells, that is, connexin43 (Cx43) and connexin37 (Cx37). In addition, the electrophysiological criteria that distinguish heteromeric connexins from their heterotypic and homotypic counterparts are reviewed, as along with the potential physiological relevance of heteromeric channels to tissue function in situ.