Taking Apart the Gating of Voltage-Gated K+ Channels

؉ Channels labeling studies of KcsA suggest that K ϩ channels may gate by rotating the inner helices that line the pore (Per-ozo et al., 1999). In this model, the degree of rotation of the helices regulates the aperture of the inner mouth of the pore that opens and closes like the shutters of a San Francisco, California 94143 camera. For voltage-gated K ϩ channels, this model is broadly consistent with measurements of the state-dependent reactivity of cysteines in S6 and the identifi-Voltage-gated ion channels constitute a subset of ion cation of mutations that affect gating in this region (for channels that are intrinsically sensitive to changes in the review, see Yellen, 1998). membrane potential. Like clockwork, these ion channels A second gate uses the N-terminal tip of the voltage-open and close to generate complex electrical signals, gated K ϩ channel protein and is hence termed N-type such as action potentials, in neurons and other excitable inactivation. N-type inactivation closes the channel dur-cells. How voltage-gated ion channels " sense " changes ing long, sustained depolarizations and works by a " ball-in the membrane potential and the mechanism by which and-chain " mechanism. The opening of the activation those changes are translated into channel gating, the gates is believed to create a binding site for the extreme conformational changes that allow channels to open and N terminus to enter and occlude the inner mouth of the close, are questions that have fascinated researchers for pore. A third gate, responsible for C-type inactivation, decades. is located at the outer mouth of the pore and works Avid readers of classic papers will recognize that by collapsing the pore selectivity filter. In Shaker K ϩ Hodgkin and Huxley, realizing that a molecular descrip-channels, N-type inactivation is generally faster than tion for the ionic currents they observed was out of their C-type inactivation; therefore, they are also referred to reach, posed these questions in 1952. Today, a direct as fast and slow inactivation, respectively. In some K ϩ approach to solving this problem might seem transpar-channels, however, C-type inactivation can be fast. ent, if not venturesome. A crystal structure of a voltage-HERG channels, for example, display a fast form of gated ion channel in the closed state and the open state C-type inactivation that plays a part in determining its would give a detailed picture of how the channel works. physiological role in the repolarization …