2001 UW AMC Dean's Report

The body’s cells signal by electricity. At the core of the electrical signaling system are ion channels—pores in cell membranes that selectively open and close to allow the passage of millions of electrically charged molecules. Such diseases as epilepsy, cystic fibrosis, and cardiac arrhythmia occur when ion channels send the wrong signals. Migraine headaches may occur the same way.

UW scientists have made many important discoveries about ion channels—protein molecules responsible for generating electrical signals in cells. In pioneering work in the 1970s, Dr. Bertil Hille, professor of physiology and biophysics, analyzed the electrical signals produced by ion channels in nerves in great detail, and proposed mechanistic models for their function. These models still remain relevant.

In 1980, Dr. William Catterall, professor and chair of pharmacology, identified ion channel molecules for the first time, specifically the protein subunits of the sodium channel—the molecule that initiates and transmits electrical signals to the brain. The brain uses these electrical signals in process and store information and to control vital bodily functions such as heartbeat, muscle movement, and hormone secretion.

The implications for drug therapies are enormous. The Human Genome Project has identified some 200 ion channel genes, each of which makes different proteins that could be the target of drugs. Local anesthetics like Novocain, for example, and many other drugs work by controlling ion channels.

The construction of this molecular model of the brain sodium channel is based on the three-dimensional structure of a small bacterial potassium channel analyzed by Dr. Rod MacKinnon of Rockefeller University.

“In our early work, we wanted to understand the protein molecules that carry out the functions of ion channels,” Catterall said. Four years after discovering the protein subunits of the sodium channels, he identified the subunits of the calcium channel, which ultimately control heart rhythm, blood pressure, and other functions by initiating contraction in muscle tissues. In 1988—working with Dr. Todd Scheuer, now research associate professor of pharmacology—Catterall identified the inactivation gate of the sodium channel, the gate that controls rapid closure of the channel. The researchers also identified the target site for local anesthetic, antiarrhythmic, and anti-convulsant drugs used for pain relief, therapy of cardiac arrhythmias, and epileptic seizures.

Several labs have now cloned genes for sodium and calcium channels. Others have discovered potassium channels. By studying molecules and genes, researchers are able to connect ion channel proteins to their functions. New work is shedding light on the relationship between ion channel abnormalities and diseases such as cystic fibrosis, in which chloride channels malfunction; cardiac arrhythmia and epilepsy, in which sodium channels malfunction; and certain forms of muscular paralysis, which involve abnormal sodium, calcium, or chloride channels in skeletal muscle cells.

At a weekly conference, Dr. Catterall and Dr. Todd Scheuer listen to a presentation by a member of their research group.

Catterall and Scheuer have used neurotoxins produced by scorpions and sea anemones to study the molecular structure and function of ion channels, and how the neurotoxins attack the nervous system. Their work has also mapped in great detail the small region on ion channel proteins where drug molecules bind. It is hoped that detailed information on the drug-binding region will allow development of improved therapeutic agents.

Catterall received the Passano Foundation Young Scientist Award in 1981, the Jacob Javits Neuroscience Investigator Award in 1984 and 1991 and the American Heart Association’s Basic Science Prize in 1992. He is a member of the National Academy of Sciences, where he served as chair of the Section of Physiology and Pharmacology from 1998 to 2001. In 2000 he was elected to membership in the Institute of Medicine.