Gap junctions, formed by the connexin family of proteins, span the membranes of and provide electrical continuity between adjacent cells. These channels allow the passage not only of ions, but also of molecules as large as second messengers. Most connexin channels have a voltage-sensitive gate, which closes when a voltage difference develops between cells. However, this closure is partial, and would not be expected to break the electrical continuity of the cells. So, what is the function of the voltage gate? In a recent report, Qu and Dahl provide some clues.

Gap junctions have at least two conductance states: the 'full conductance' state and a 'subconductance' state. Rather than closing completely, these channels spend longer periods of time in the subconductance state when the gate senses a voltage change. Qu and Dahl considered the possibility that channel selectivity in this state might differ from that in the full conductance state such that the passage of larger molecules would be reduced. In this way, the activated gate would allow electrical coupling, while obstructing the passage of metabolites and second messengers.

To test this idea, the authors expressed connexin 46 (Cx46) or Cx43 in Xenopus oocytes. They monitored the passage of fluorescent test molecules or cyclic AMP through Cx46 hemichannels expressed in single oocytes, and through full heterotypic (Cx46/Cx43) channels that formed between cells.

By recording from single Cx46 hemichannels, Qu and Dahl confirmed that the subconductance state predominates at positive holding potentials (+20 to +30 mV) compared with negative potentials (−30 to −20 mV). But when oocytes that expressed Cx46 were clamped at +20 mV (that is, when channels were induced to 'close'), the macroscopic membrane conductance was found to be higher than that recorded at −20 mV, presumably because there was an overall increase in the open time of the channel. However, the flux of fluorescent molecules or cAMP was greatly diminished by depolarization. Moreover, the flow of cAMP through Cx46/Cx43 channels was reduced when a voltage was applied across the junction. So, whereas the passage of small ions is largely undisturbed, the transit of larger molecules is reduced when the voltage gate is activated.

What is the physiological effect of this change in permeability? Qu and Dahl suggest that the gate might prevent the accumulation of charged molecules in parts of a tissue in the presence of an electrical field. As electrical synapses are present in many parts of the nervous system, this property of gap junctions might have a particularly important role in neuronal signalling.