Coupled Movements in Voltage-gated Ion Channels

Ion channels, like most other proteins, are designed to move. To preserve ionic gradients across cell membranes , they are usually closed and open their gates only when called upon to do electric work. Ionic fluxes through open channels are exploited by cells for a variety of tasks, including the generation of explosive action potentials in excitable cells. A singular feature of the ion channels underlying action potentials is that their gates are regulated by the voltage across the plasma membrane. Membrane potential has two roles in voltage-gated ion channels. It controls the open probability of their gates, especially the so-called activation gate, and it drives ions through open channels. The activation gate in this class of ion channel tends to be highly sensitive to small changes in membrane potential, so much so that a depolarization of only 5 mV can produce a 10-fold increase of open probability (Schoppa et al., 1992; Hirschberg et al., 1995). What underlies this exquisite sensitivity? Three functional components of the channel are required: a per-meation pathway (pore), gates that permit or deny the movement of ions through the pore, and a voltage sensor that changes its conformation in response to changes of membrane potential. Movement of the voltage sensor must be coupled energetically to the gates. The steep voltage dependence of activation in many types of potassium channels requires that at least 12 elementary charges (e 0) cross the membrane electric field between completely closed and open conforma-tions (Sigworth, 1994; Sigg and Bezanilla, 1997). The energetic coupling between membrane potential and the activation gate is the defining characteristic that makes these channels voltage dependent. Nature chose to make the voltage sensor and the activation gate separate structures. It didn't have to be that way. If the activation gate were sufficiently charged and moved through the electric field as it opened and closed, it would also serve as a voltage sensor. However, the activation gate is formed by the cytoplasmic convergence of four uncharged transmembrane segments (S6 segments) that line the pore (Liu et al., 1997; Del Ca-mino et al., 2000; Del Camino and Yellen, 2001). These S6 segments are contributed either from four separate ␣ subunits in potassium channels, or from each of four homologous domains on a single ␣ subunit in sodium and calcium channels. Even an uncharged gate can itself cause charge movement across the electric field when it opens or closes …