There are ion channels specific for K+, Na+, Ca2+, and Cl–, as well as channels that are nonselective for cations or anions. Each type of channel exists in multiple forms with diverse properties. Most are made up of identical or very similar sub units. Figure 1 shows the multiunit structure of various channels in diagrammatic cross-section.
Fig1. Different ways in which ion channels form pores. A) Four subunits form a central pore in typical K+ channels. B) Some ligand-gated channels such as the acetylcholine receptor contain five similar subunits that form a central pore in the channel. C) Aquaporin, or water channels, contain four subunits that each contain a pore that can allow for water movement. Additionally, these subunits form a central pore that can allow for ion movement. It should be noted that other formations also occur.
Most K+ channels are tetramers, with each of the four sub units forming part of the pore through which K+ ions pass. Structural analysis of a bacterial voltage-gated K+ channel indicates that each of the four subunits have a paddle-like extension containing four charges. When the channel is closed, these extensions are near the negatively charged inte rior of the cell. When the membrane potential is reduced, the paddles containing the charges bend through the membrane to its exterior surface, causing the channel to open. The bacte rial K+ channel is very similar to the voltage-gated K+ channels in a wide variety of species, including mammals. In the acetylcholine ion channel and other ligand-gated cation or anion channels, five subunits make up the pore. Members of the ClC family of Cl– channels are dimers, but they have two pores, one in each subunit. Finally, aquaporins are tetramers with a water pore in each of the subunits. Recently, a number of ion channels with intrinsic enzyme activity have been cloned. More than 30 different voltage-gated or cyclic nucleotide-gated Na+ and Ca2+ channels of this type have been described. Representative Na+, Ca2+, and K+ channels are shown in extended diagrammatic form in Figure 2.
Fig2. Diagrammatic representation of the pore-forming subunits of three ion channels. The α subunit of the Na+ and Ca2+ channels traverse the membrane 24 times in four repeats of six membrane-spanning units. Each repeat has a “P” loop between membrane spans 5 and 6 that does not traverse the membrane. These P loops are thought to form the pore. Note that span 4 of each repeat is colored in red, representing its net “+” charge. The K+ channel has only a single repeat of the six spanning regions and P loop. Four K+ subunits are assembled for a functional K+ channel. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ (editors): Principles of Neural Science, 5th ed. New York, NY: McGraw-Hill; 2013.)
Another family of Na+ channels with a different structure has been found in the apical membranes of epithelial cells in the kidneys, colon, lungs, and brain. The epithelial sodium channels (ENaCs) are made up of three subunits encoded by three different genes. Each of the subunits prob ably spans the membrane twice, and the amino terminal and carboxyl terminal are located inside the cell. The α sub unit transports Na+, whereas the β and γ subunits do not. However, the addition of the β and γ subunits increases Na+ transport through the α subunit. ENaCs are inhibited by the diuretic amiloride, which binds to the α subunit, and they used to be called amiloride inhibitable Na+ channels. The ENaCs in the kidney play an important role in the regulation of ECF volume by aldosterone. ENaC knockout mice are born alive but promptly die because they cannot move Na+, and hence water, out of their lungs.
Humans have several types of Cl– channels. The ClC dimeric channels are found in plants, bacteria, and animals, and there are nine different ClC genes in humans. Other Cl– channels have the same pentameric form as the acetylcholine receptor; examples include the γ-aminobutyric acid A (GABAA ) and glycine receptors in the CNS. The cystic fibro sis transmembrane conductance regulator (CFTR) that is mutated in cystic fibrosis is also a Cl– channel. Ion channel mutations cause a variety of channelopathies—diseases that mostly affect muscle and brain tissue and produce episodic paralyses or convulsions, but are also observed in nonexcitable tissues (Clinical Box 2–6).
