All Voltage Gated Ion Channels Have Similar Structures

Having explained how the action potential is dependent on regulated opening and closing of voltage-gated channels, we turn to a molecular dissection of these remarkable proteins. After describing the basic structure of these channels, we focus on three questions:

■ How do these proteins sense changes in membrane potential?

■ How is this change transduced into opening of the channel?

■ What causes these channels to become inactivated shortly after opening?

The initial breakthrough in understanding voltage-gated ion channels came from analysis of fruit flies (Drosophila melanogaster) carrying the shaker mutation. These flies shake vigorously under ether anesthesia, reflecting a loss of motor control and a defect in certain motor neurons that have an abnormally prolonged action potential. This pheno-type suggested that the shaker mutation causes a defect in voltage-gated K+ channels that prevents them from opening normally immediately upon depolarization. To show that the wild-type shaker gene encoded a K+ channel, cloned wildtype shaker cDNA was used as a template to produce shaker mRNA in a cell-free system. Expression of this mRNA in frog oocytes and patch-clamp measurements on the newly synthesized channel protein showed that its functional properties were identical to those of the voltage-gated K+ channel in the neuronal membrane, demonstrating conclusively that the shaker gene encodes this K+-channel protein.

The Shaker K+ channel and most other voltage-gated K+ channels that have been identified are tetrameric proteins composed of four identical subunits arranged in the membrane around a central pore. Each subunit is constructed of six membrane-spanning a helixes, designated S1-S6, and a P segment (Figure 7-36a). The S5 and S6 helices and the P segment are structurally and functionally homologous to those in the nongated resting K+ channel discussed earlier (see Figure 7-15). The S4 helix, which contains numerous positively charged lysine and arginine residues, acts as a voltage sensor; the N-terminal "ball" extending into the cytosol from S1 is the channel-inactivating segment.

Voltage-gated Na+ channels and Ca2+ channels are monomeric proteins organized into four homologous domains, I-IV (Figure 7-36b). Each of these domains is similar to a subunit of a voltage-gated K+ channel. However, in contrast to voltage-gated K+ channels, which have four channel-inactivating segments, the monomeric voltage-gated channels have a single channel-inactivating segment. Except for this minor structural difference and their varying ion permeabilities, all voltage-gated ion channels are thought to function in a similar manner and to have evolved from a monomeric ancestral channel protein that contained six transmembrane a helices.

M FIGURE 7-36 Schematic depictions of the secondary structures of voltage-gated K+ and Na+ channels. (a) Voltage-gated K+ channels are composed of four identical subunits, each containing 600-700 amino acids, and six membrane-spanning a helices, S1-S6. The N-terminus of each subunit, located in the cytosol, forms a globular domain (orange ball) essential for inactivation of the open channel. The S5 and S6 helices (green) and the P segment (blue) are homologous to those in nongated resting K+ channels, but each subunit contains four additional transmembrane a helices. One of these, S4 (red), is the voltage-sensing a helix. (b) Voltage-gated Na+ channels are monomers containing 1800-2000 amino acids organized into four transmembrane domains (I—IV) that are similar to the subunits in voltage-gated K+ channels. The single channel-inactivating segment, located in the cytosol between domains III and IV, contains a conserved hydrophobic motif (H). Voltage-gated Ca2+ channels have a similar overall structure. Most voltage-gated ion channels also contain regulatory (p) subunits that are not depicted here. [Part (a) adapted from C. Miller, 1992, Curr. Biol. 2:573, and H. Larsson et al., 1996, Neuron 16:387 Part (b) adapted from W. A. Catterall, 2001, Nature 409:988.]

(a) Voltage-gated K+ channel (tetramer)

(a) Voltage-gated K+ channel (tetramer)

(b) Voltage-gated Na+ channel (monomer)
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