In this chapter, we have explained the action of specific membrane transport proteins and their impact on certain aspects of human physiology; such a molecular physiology approach has many medical applications. Even today, specific inhibitors or activators of channels, pumps, and transporters constitute the largest single class of drugs. For instance, an inhibitor of the gastric H⁺/K⁺ ATPase that acidifies the stomach is the most widely used drug for treating stomach ulcers and gastric reflux syndrome. Inhibitors of channel proteins in the kidney are widely used to control hypertension (high blood pressure); by blocking resorption of water into the blood from urine forming in the kidneys, these drugs reduce blood volume and thus blood pressure. Calcium-channel blockers are widely employed to control the intensity of contraction of the heart. Drugs that inhibit a particular potassium channel in β islet cells enhance secretion of insulin (see Figure 16-39) and are widely used to treat adult-onset (type II) diabetes. Ion channels are also the major targets of drugs for helminthic diseases that afflict over a billion people worldwide. These drugs achieve their specificity by targeting ion channels in the parasitic worms without affecting the homologous channels in humans.

With the completion of the Human Genome Project, we have in hand the sequences of all human membrane transport proteins. Already we know that mutations in many of them cause disease—cystic fibrosis, due to mutations in CFTR, is one example, and osteopetrosis, caused by mutations in the ClC-7 chloride channel, is another. More recently it has been shown that loss-of-function mutations in either subunit of a different chloride channel, ClC-K, cause both salt loss by the kidney and deafness. This explosion of basic knowledge, associating specific genetic diseases with specific transport proteins, will enable researchers to identify new types of compounds that inhibit or activate just one of these membrane transport proteins and not its homologs.

The development of protein structure–based therapies depends on the elucidation of the structures of membrane transport proteins. Because membrane proteins are notoriously difficult to crystallize, determining their three-dimensional structures using traditional x-ray crystallography techniques has been challenging. Even though over 30 percent of the human genome encodes membrane proteins, and even though 50 percent of therapeutic drugs target membrane proteins, as of the end of 2014, less than 1 percent of determined protein structures were of membrane proteins! Recent successes in determining high-resolution structures of membrane proteins using cryoelectron microscopy and micro-electron diffraction indicate that these methods will open the door to solving the structures of many membrane transport proteins, which will in turn lead to the development of small-molecule therapies that specifically target disease-causing mutations. In addition, the new field of molecular dynamics, which involves computer simulation of atomic and molecular movements, is providing insights into the conformational changes that underlie the function of membrane transport proteins.

One major challenge for future studies is to understand how each channel, transporter, and pump is regulated to meet the needs of the cell. Like other cellular proteins, many of these proteins undergo reversible phosphorylation, ubiquitinylation, and other covalent modifications, including reversible association with interacting proteins and lipids, that affect their activity. However, in the vast majority of cases, we do not understand how this regulation affects cellular function. Many channels, transporters, and pumps normally reside on intracellular membranes, not on the plasma membrane, and move to the plasma membrane only when a particular hormone is present. The addition of insulin to muscle, for instance, causes the GLUT4 glucose transporter to move from intracellular membranes to the plasma membrane, increasing the rate of glucose uptake. We noted earlier that the addition of vasopressin to certain kidney cells similarly causes an aquaporin to move to the plasma membrane, increasing the rate of water transport. But despite much research, we still have little understanding of the underlying cellular mechanisms by which hormones stimulate the movement of transport proteins to and from the plasma membrane, or of the regulation of these processes.