Ion Channels: Not an Open and Shut Case

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Ion channels, proteins that regulate the transfer of ions across the cell membrane, can be broadly classified according to ‘gating mechanism’ – what makes the channel open and close. Voltage-gated channels respond to a voltage gradient across the plasma membrane whereas ligand-gated channels are activated by binding of extracellular ligands or intracellular second messengers. Recent detailed studies of ion channels are showing, however, that things are not quite so simple.

Researchers in the US and Germany have now shown that they can confer significant voltage dependence to the inwardly rectifying K+ channel, Kir6.2, by introducing a point mutation, L157E. Kir6.2 is a ligand-gated channel that lacks a canonical voltage-sensing domain (VSD). In classical models of voltage-dependent gating, the VSD strongly influences opening and closing of the pore-forming domain so that the channel open probability is reduced to virtually zero at sufficiently negative voltages and increased to near unity upon depolarization. Previous observations have shown that such ‘tight coupling’ between the VSD and the pore does not apply to all channel types and the new study shows that substitution of charged residues at pore-lining positions can affect channel gating in very unexpected ways. Comparing Kir6.2[L157E] with wild type Kir6.2, the team found that the probability of opening under conditions of low intracellular K+ was much greater for the mutant channel. The presence of a natural ligand, phosphatidyl inositol bis-phosphate (PIP2), removed the voltage dependence of the mutant channel. Both voltage- and ligand-dependent gating of Kir6.2[L157E] were highly sensitive to intracellular [K+], indicating an interaction between ion permeation and gating.

The authors of the study, which is published in PLoS Biology, propose that ions flowing through the ion channel pore can significantly affect channel activity and that the mechanisms of voltage-gating and ligand-gating may be more closely linked than previously supposed. They further suggest that such interactions are likely to be a general, if latent, feature of the superfamily of cation channels.


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