Poorly understood cell-surface channels implicated in wide range of human diseases

February 16, 2006

(SACRAMENTO, Calif.) — Nearly one-third of human genes are responsible for making cell-wall proteins, half of which are gatekeeper molecules called ion channels. These channels change shape to form passable canals — allowing, among other things, for brain cells to communicate with one another and heart muscle cells to control the rhythm of our heartbeats. Scientists long suspected that defective versions of these channels were the root cause of a variety of human diseases, but only recently have they been able to study them in great detail. That ability has opened up a whole new area of research with wide-ranging implications for treating diseases in the future.

Researchers at the UC Davis School of Medicine are helping to lay the groundwork for future treatment of everything from juvenile diabetes to muscular dystrophy by revealing the structure, function and distribution of these important channels. They will be presenting some of their most promising findings on February 22 as part of the first annual Joseph Silva Jr. Basic Science Lectureship series. The lecture series is named in honor of the emeritus dean of the school, whose leadership contributed to a 116 percent growth in research.

The man who helped to usher in this new focus on ion channels, Peter Agre, will deliver the day's keynote address. In 2003, Agre was awarded the Nobel Prize in Chemistry for discovering the water channel — dubbed “water pore” or aquaporin — that regulates and facilitates the movement of water molecules through cell membranes.

Until Agre's discovery, scientists could not explain how water — the most ubiquitous molecule in the human body — moved in and out of cells.

“We had to do a lot of hand waving,” said Peter Cala, chair of the Department of Physiology and Membrane Biology at the school.

According to Cala, the time is right for major advancements in the field.

“This is a very exciting time. We have more sophisticated biochemical and molecular techniques and the latest imaging technology at our disposal,” he said.

For example, Jie Zheng, an assistant professor in the department, uses fluorescent imaging to describe the way chloride channels in the cells of the shock-producing organs of electric rays change shape when opening and closing. In humans, chloride channels have been implicated in certain forms of well-known diseases, including muscular dystrophy, epilepsy and osteoporosis.

In doing his work, Zheng attaches light-emitting molecules called fluorophores to channel proteins while they are embedded in cell membranes. When the protein makes even the smallest move, the fluorophore emits a fluorescent signal that Zheng measures.

Previously, scientists could only measure channel activity when the channel was at its final open stage and releasing charged particles. They knew, however, that these molecules had to go through many stages in order to change their complex shapes.

“With fluorescent recording, it is possible for us to see those earlier steps,” Zheng explained.

Finding solid models for studying channels has been among the challenges for scientists, said Crina Nimigean, also an assistant professor in physiology and membrane biology. She is using traditional X-ray crystallization and biochemical methods to study a type of channel that plays a role in the heart's pacemaker activity and eye sight.

Nimigean and other scientists have had to turn to bacteria to study these cyclic nucleotide-gated, or CNG, channels because they are difficult to extract and crystallize from animal cells.

“We can study the channels of bacteria in ways that are prohibitive with mammalian cells, which is why we are concentrating on the bacteria for now,” Nimigean said.

Still, other researchers are using descriptions of how channels work to blocking their function in order to treat disease. Heike Wulff, for example, has found that one of the 75 kinds of potassium channels found in humans is overly abundant in immune cells — called T-cells — that have gone awry. These cells are responsible for attacking the body's healthy tissues and causing several autoimmune diseases, like Type 1 diabetes, rheumatoid arthritis and multiple sclerosis.

“What we've done is describe the over-expression of this channel in pathogenic T-cells, and we've found a small molecule that can block this channel,” said Wulff, an assistant professor of medical pharmacology and toxicology. The molecule Wulff found — and is now testing in animal models — comes from the plant used to make rue tea, previously used by herbalists to lessen the symptoms of multiple sclerosis patients.”

Wulff's work, Cala said, is an example of the kind of translational research that will become more common as scientists continue to study and understand how ion channels work.

“With this knowledge, you can make a laser hit instead of using the shotgun approach to developing new drugs. Now, you'll know what you're aiming at,” he said.

As a premier academic medical center, UC Davis Health System's mission is to discover and share knowledge to advance health. Nearly 650 research studies — including basic science, translational and clinical research — are under way. Funded by the federal and state government, as well as private foundations, and the pharmaceutical and biotechnology industries, research includes some of the health system's most innovative programs in the area of cancer, infectious diseases, neurosciences, vascular biology, stem cells, epidemiology, health disparities and human molecular genetics.