The connexin family of intercellular channel forming proteins

Adjacent cells share ions, second messengers and small metabolites through intercellular channels which are present in gap junctions. This type of intercellular communication permits coordinated cellular activity, including contraction of cardiac and smooth muscle [1–5], transmission of neuronal signals at electrotonic synapses [6, 7], and regulated secretion in both the exocrine and endocrine pancreas [8, 9]. In addition, gap junctional communication may also play important roles in pattern formation during development [10] and control of cell growth [11]. Gap junctions are observed where the plasma membranes of adjacent cells come into close apposition [12]. In freeze fracture images, the gap junction appears as a dense array of particles in the plasma membrane of one cell, with corresponding pits in the membrane of the adjacent cell (Fig. 1A; [13]). Analysis of isolated gap junctions by X-ray diffraction indicates that each of the particles observed by freeze fracture corresponds to half of an intercellular channel, called the connexon. Two connexons align in the extracellular space to form a complete intercellular channel, providing a relatively large hydrated pore between the cytoplasm of the communicating cells (Fig. 1B)[14,15]. Each connexon is an oligomer of subunit proteins, called connexins. Current nomenclature appends the molecular mass predicted by cloned DNA sequences to the family name connexin (Cx). For example, the 43 kD protein first identified in myocardial gap junctions is termed Cx43 [16]. Connexin homologues from different organisms are distinguished with a suitable identifying prefix. The connexins are a multigene family with a complex tissue distribution. Multiple connexins are often present in the same cell type, and can even be in the same gap junctional plaque [17–19]. The size of the connexin family greatly complicates interpretation of how multiple connexins interact in a tissue to coordinate function. In the lens, there are only two differentiated cell types which express three connexins, making it one of the least complicated systems in which to study intercellular communication [20]. In contrast, skin is a more representative organ, utilizing at least five different connexins in a complex and developmentally regulated pattern of expression [21, 22]. The kidney provides an excellent example of the current challenge in relating connexin diversity to organ homeostasis. Gap junctions are present in the multiple cell types in the renal vasculature, the juxtaglomerular apparatus, the glomerulus, the proximal and distal convoluted tubules and the collecting ducts [23–29]. The kidney expresses mRNA for connexins 26, 32, 37, 40, 43, 45, and 46 [16, 19, 30–33] and the expression of some of these connexins is developmentally regulated [33–35]. The localization of only three of these seven connexins is known in the developing and adult rodent kidney. Cx26 and Cx32 first appear in the proximal tubules of 17 days mouse embryos, and are abundant in all proximal tubules after birth. Cx43 is first detected in the mesenchemal cells of 12-day-old embryonic mouse kidney and is widely expressed in the early tubule cells of the developing nephron. Cx43 is then down-regulated, and in the adult tissue is broadly distributed, with the greatest abundance in the collecting ducts [34, 36]. The cellular localization of the other four connexins which are expressed in kidney is not currently known.