Connexins: functions without junctions
Introduction
Gap junctions are composed of intercellular channels that span two plasma membranes and provide a direct pathway for the movement of signaling molecules and ionic currents between adjacent cells. To form the intercellular channel, neighboring cells contribute subunits called connexons or hemichannels that associate in the narrow extracellular space between adjacent plasma membranes. The hemichannels are composed of connexins, a mid-sized family of highly related proteins. Forward and reverse genetic approaches have established that gap junctions critically influence many cellular behaviors (for review, see [1]). However, the most surprising findings of the past few years indicate that connexins have critical functions that don’t involve intercellular channels and, conversely, that connexins are not the only proteins capable of forming intercellular channels.
Section snippets
Gap junctions not required
Recent studies suggest that connexin hemichannels can display activity in single plasma membranes, introducing large ionic conductances and dramatically changing the permeability properties of individual cells. Although the in vivo functions of hemichannels are still being debated, their activity has been linked to a surprising number of physiological and pathophysiological events.
Channel activity not required
Are connexins involved in functions not directly associated with their channel forming ability? Several lines of evidence suggest they are.
Since most transformed cells do not establish gap junctions, it was suggested many years ago that junctional communication might influence proliferation. Subsequently, many studies have correlated the suppression of growth in transformed cells with restoration of communication, typically by connexin transfection. Paradoxically, it appears that in some cases
Connexins, innexins and pannexins
A truly unexpected finding in recent years was that vertebrate and invertebrate organisms use completely unrelated gene families to encode gap junction proteins. Gap junctions in mammals, teleosts and amphibians contain connexins whereas arthropod and nematode gap junctions contain ‘innexins’ (invertebrate connexins). This may be the only case in which a metazoan channel protein is not conserved across different phyla. Connexins and innexins share no primary sequence homology and their
Conclusions
It is now clear that both connexins and pannexins can form hemichannels that introduce large, relatively non-selective conductances in single plasma membranes. However, almost all demonstrations thus far involve cultured cells and the evidence regarding physiological or pathophysiological significance remains correlative. The next goals include direct structural and physiologic demonstrations of hemichannels in intact tissues. Furthermore, it is necessary to develop methods of separating the
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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2019, Cell ReportsCitation Excerpt :GJ intercellular communication (GJIC) exchanges ions, microRNAs (miRNAs), small metabolites such as glucose, antioxidants, and peptides between cells, allowing them to coordinate their phenotypes and respond to environmental conditions (Goodenough and Paul, 2009). Connexin proteins serve three main cellular functions: exchange of small molecules between cells as GJs, exchange of small molecules between a cell and the extracellular space as hemichannels, and binding to intracellular proteins (Goodenough and Paul, 2003, 2009; Leithe et al., 2018; Stout et al., 2004). Previous work based mainly on connexin 43 (Cx43) suggested that connexins act as tumor suppressors (Aasen et al., 2016).
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