Yet another member of the ABC transporter family is the cystic fibrosis trans-membrane conductance regulator protein (CFTR), which was discovered through studies of the common genetic disease cystic fibrosis. This disease is caused by a mutation in the gene encoding CFTR, a Cl– transport protein in the plasma membrane of epithelial cells. CFTR regulates ion concentrations in the extracellular fluid, especially in the lung. One in 27 Caucasians carries a gene encoding a mutant form of this protein; in 1 in 2900, both copies of the gene are mutated, causing the disease. In contrast to other ABC transporters, ATP binding and hydrolysis in the CFTR protein do not drive the transport process. Instead, they control the opening and closing of a continuous channel, which provides a passive conduit for Cl– to move down its electrochemical gradient. Thus, some ABC proteins can function as transporters and others as gated channels.
Transporters bind specific solutes and transfer them across the lipid bilayer by undergoing conformational changes that alternately expose the solute-binding site on one side of the membrane and then on the other. Some transporters move a single solute “downhill,” whereas others can act as pumps to move a solute “uphill” against its electrochemical gradient, using energy provided by ATP hydrolysis, by a downhill flow of another solute (such as Na+ or H+), or by light to drive the requisite series of conformational changes in an orderly manner. Transporters belong to a small number of protein families. Each family evolved from a common ancestral protein, and its members all operate by a similar mechanism. The family of P-type transport ATPases, which includes Ca2+ and Na+-K+ pumps, is an important example; each of these ATPases sequentially phosphorylates and dephosphorylates itself during the pumping cycle. The superfamily of ABC transporters is the largest family of membrane transport proteins and is especially important clinically. It includes proteins that are responsible for cystic fibrosis, for drug resistance in both cancer cells and malaria-causing parasites, and for pumping pathogen-derived peptides into the ER for cytotoxic lymphocytes to reorganize on the surface of infected cells.
Unlike transporters, channels form pores across membranes. One class of channel proteins found in virtually all animals forms gap junctions between adjacent cells; each plasma membrane contributes equally to the formation of the channel, which connects the cytoplasm of the two cells. These channels are discussed in Chapter 19 and will not be considered further here. Both gap junctions and porins, the channels in the outer membranes of bacteria, mitochondria, and chloroplasts (discussed in Chapter 10), have relatively large and permissive pores, and it would be disastrous if they directly connected the inside of a cell to an extracellular space. Indeed, many bacterial toxins do exactly that to kill other cells (discussed in Chapter 24).
In contrast, most channels in the plasma membrane of animal and plant cells that connect the cytosol to the cell exterior necessarily have narrow, highly selective pores that can open and close rapidly. Because these proteins are concerned specifically with inorganic ion transport, they are referred to as ion channels. For transport efficiency, ion channels have an advantage over transporters, in that they can pass up to 100 million ions through one open channel each second—a rate 105 times greater than the fastest rate of transport mediated by any known transporter. As discussed earlier, however, channels cannot be coupled to an energy source to perform active transport, so the transport they mediate is always passive (downhill). Thus, the function of ion channels is to allow specific inorganic ions—primarily Na+, K+, Ca2+, or Cl–—to diffuse rapidly down their electrochemical gradients across the lipid bilayer. In this section, we will see that the ability to control ion fluxes through these channels is essential for many cell functions. Nerve cells (neurons), in particular, have made a specialty of using ion channels, and we will consider how they use many different ion channels to receive, conduct, and transmit signals. Before we discuss ion channels, however, we briefly consider the aquaporin water channels that we mentioned earlier.