Watching Ion Channels on the Move.

Ion channels remain fascinating molecular machines implicated in virtually every cellular function. Their activity can be studied in deep detail using biophysical techniques down to the single-molecule level. However, as large hydrophobic proteins embedded in a lipidic environment, their structure has traditionally been very difficult to study. Cryo-EM approaches have boosted our knowledge in the last few years, expanding the collection of resolved structures almost on a weekly basis. Yet, there are still open questions regarding the structure-function of the channels that are now starting to find answers. Ion channels react rapidly to a wide range of stimuli, opening a pathway for the flow of ions across the membrane. The coupling of the stimulus to the opening of the gate can be studied in ligand-gated channels by comparing the structures of the ligand-bound and unbound channels. Still, such a comparison is more difficult to achieve when the channel responds to physical rather than chemical stimuli, as is the case of voltage-gated channels. The molecular principles of voltage-dependent gating of ion channels have been known for four decades. The mechanism consists, in essence, of the movement of some parts of the protein (the voltage-sensing domains) relative to others. The displacement results in a conformational change that produces the opening of the gate, but the intimate molecular mechanisms linking both events remain only partly known in many cases. Although the problem might appear like an academic discussion for experts at first glance, it has many practical implications. On the one hand—mainly