Like an intricate electrical switchboard, the nervous system carries billions of electrical signals throughout the body. Besides transmitting information between nerve cells, electrical signals also regulate the secretion of hormones and coordinate the contraction of skeletal and heart muscles.
The gates that pass along the information are tiny pores in the cell's outer membrane. These structures, called ion channels, are like molecular pores that open and close in response to stimuli. Opening and closing like tiny gates, they allow electrically charged atoms--such as sodium, potassium, and calcium ions--to pass in and out of the cell through the cell's outer membrane. Much like the transistors of electronic circuits, ion channels make, shape, and send these fleeting electrical signals, enabling cells to communicate with one another.
In 1980, William A. Catterall of the UW pharmacology department became the first researcher to identify the protein subunits of sodium channels. And four years later, he identified the subunits of the calcium channel, which ultimately controls heart rhythm and blood pressure, among other physiological functions.
Normal electrical signaling in the nervous system requires that the current be turned on and off. In 1988, Catterall identified the inactivation gate of the sodium channel, which switches the electrical current off. The inactivation gate closes the sodium channel about one millisecond after it opens.
Another UW researcher, professor of physiology and biophysics Bertil Hille, was among the first neuroscientists to describe the size, shape, and function of ion channels, publishing on sodium channel physiology in 1966. Prior to that time, scientists believed ions flowed anywhere across the cell membrane.
"We originally thought that only nerve cells had ion channels," notes Hille, who published the first book on ion channels, Ionic Channels in Excitable Membranes, in 1984. "Then we added muscle cells, and now we know that every cell has ion channels and makes signals and uses them." In 1977, Hille elucidated the molecular action of local anesthetics on their target, the sodium channel; and in 1994, Catterall and pharmacology researcher Todd Scheuer identified the receptor site on the sodium channel where the local anesthetics act.
Although ion channels open and close in milliseconds, their activity is regulated over longer time scales—minutes, hours, and days—by hormones and other cellular regulators. In 1985, Hille and pharmacology professor Neil Nathanson found that hormonal regulation of a potassium channel in the heart is caused by activation of so-called G proteins, a family of intracellular regulators that carry out the actions of many hormones. This regulatory pathway is now known to be important in regulation of ion channels in many different types of cells.
New work at the UW is shedding light on the relationship between ion channel abnormalities and diseases such as cystic fibrosis, in which the chloride channels malfunction; some bacterial infections like cholera, that alter ion channel function; and certain forms of muscular dystrophy, which involve abnormal channels in specific muscle cells.
Catterall has made use of exotic neurotoxins produced by scorpions and sea anemones to study the molecular structure and functions of ion channels. He and his colleagues are trying to map the function of each part of the ion channel protein and to identify the parts upon which drugs and toxins act.