The 2003 Nobel Prize in Chemistry, awarded Oct. 8, honors two researchers whose pioneering work on channels in cell membranes has elucidated how ions and water molecules get in and out of cells. Such protein-based channels or pores underlie much of physiology, from the firing of nerve cells in the brain to the regulation of water by the kidneys.
Half of the $1.3-million prize goes to Roderick MacKinnon, a Howard Hughes Medical Institute investigator at Rockefeller University in New York. In 1998, MacKinnon became the first scientist to determine the three-dimensional structure of an ion channel. Receiving the other half of the prize is Peter Agre of the Johns Hopkins University Medical Institutions. Agre was named for his discovery in the early 1990s of water channels called aquaporins.
“Everybody in this field who works on channels is elated about this award,” says biochemist Christopher Miller of Brandeis University in Waltham, Mass.
Ion channels act like valves that regulate the flow of ions, such as potassium and sodium, across a cell’s membrane. Defects in ion channels can result in myriad disorders, such as heart arrhythmia and cystic fibrosis.
Says Kenton Swartz of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., “As we begin to learn how these molecular machines work, we’ll be in a better position to design drugs that have very specific kinds of actions that might target one type of channel but not another.”
MacKinnon originally set out to discern the molecular structure of ion channels. He was undeterred by numerous failed attempts by other researchers to coax membrane-based proteins into ordered crystals.
MacKinnon and his colleagues overcame that obstacle, creating crystals of a bacterium’s potassium-channel protein. The researchers then used X-ray crystallography to generate the first high-resolution images of the channel’s structure. These data, in turn, enabled the researchers to explain how 100 million potassium ions per second can cross a cell membrane while sodium and other ions are essentially barred (SN: 3/9/02, p. 152: Channel Surfing).
MacKinnon later identified the structure of a channel that regulates the flow of chlorine ions. More recently, he uncovered the mechanism by which an ion channel opens and closes in response to a voltage across the membrane.
Agre’s discovery of the long-sought water-regulating channel was equally groundbreaking, says Miller. Aquaporins are critical for getting water into and out of cells. In the kidney, for instance, aquaporins are constantly pumping water from the organ’s many urine ducts back into cells, preventing dehydration. This process explains how the human body can generate 45 gallons of dilute urinary fluid daily and yet excrete only about one quart of urine.
Agre discovered the first aquaporin while searching for a protein on the surface of red blood cells that triggers immune responses. Instead, he found a mysterious, smaller protein. Agre and his colleagues isolated the protein and inserted the corresponding gene into frogs’ eggs. Immersed in distilled water, the eggs swelled and exploded, indicating that the protein controls the cellular flow of water.
Agre and others have since identified the structure of the water channel. Agre has also shown that defects in the genes encoding aquaporins cause many kidney disorders, as well as cataracts.
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