Connexins: functions without junctions

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Emerging studies indicate that connexins have activities completely unrelated to gap junctions and, conversely, that non-connexin proteins can form gap junction channels.

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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