How ion channels sense membrane potential

Understanding the inner workings of an ion channel has, in the last several years, boiled down to a hunt for dynamic structural cartoons that capture the essence of the channel's biophysical behavior. The main approach to this end has been the “structure–function” study in which selected residues are mutated and the functional consequences are explored electrophysiologically. Functionally important regions of the ion channel protein are often revealed from this type of experiment. Nevertheless, these studies are typically devoid of anything approaching real structural data. Therefore, the cartoon models depicting, for example, the way ion channels open and close are largely fantasies, however much insight they provide. This deficiency changed dramatically with the first crystal structure of a bacterial potassium channel (1). The significance of this scientific breakthrough included the sobering realization that standard structure–function studies can result in absurd structural predictions, highlighting the importance of atomic level structures to accompany functional studies.

The most captivating property of the ion channels responsible for action potentials in excitable cells (nerve and muscle cells) is their exquisite sensitivity to small changes of membrane potential. This is arguably the most highly scrutinized feature of these proteins since Hodgkin and Huxley (2) first described the sodium and potassium currents of the squid giant axon in 1952. However, despite a wealth of electrophysiological studies and a surfeit of discarded cartoons, the atomic structure of a voltage-gated ion channel remained elusive until 2003, when the MacKinnon laboratory obtained a crystal structure of the potassium channel KvAP (3). A functional study of KvAP by the same group led to a proposal, known as the “voltage sensor paddle model” (4), that was so surprising and apparently contradictory with a wide variety of previous experimental data that it generated an extensive controversy (e.g., see refs. 5–7) and a …