January 6, 1999
La Jolla, CA – Zinc has long been recognized as an essential trace element, and a current study led by Salk Institute investigators shows it to be an integral part of ion channels, structures that regulate communication among nerve cells.
The study, which appears in the current issue of Nature Structural Biology, may explain why zinc deficiency has been linked to cognitive impairment.
“We don’t know yet what zinc is doing, but it is definitely a component in these essential structures,” said Senyon Choe, an assistant professor at The Salk Institute for Biological Studies and senior author on the study. “And it was surprising – at first we tried to disregard it, thinking it must be a contaminant, but, of course as you try to disprove it, it keeps coming back.”
Ion channels are important “gatekeepers” that regulate the way ions such as calcium and potassium flow into and out of cells. Their flux is necessary for important neuronal processes. Calcium streams into brain cells and helps to initiate changes that accompany learning. Abnormalities in potassium channels have been found in some epileptics and in persons with both insulin-resistance and mobility disorders.
In the current study, Choe and his colleagues used X-ray crystallography to resolve the structures of four potassium channels from the sea slug Aplysia. The channels, called Shaw, Shab, Shal and Shaker, represent the four classes of potassium channels found in all higher organisms, including humans. With the exception of Shaker, all of the channels contained four zinc atoms in analogous positions.
“Each channel resembles a funnel,” said Choe, “and the zinc elements ring the end that empties into the cell’s interior.”
Neuroscientists have known for decades that dyes that bind to zinc stain brain cells in unique patterns, indicating that zinc should have a role in brain function and studies have shown that zinc can enhance learning in undernourished children. The nature of zinc’s organization in the brain, however, had been unclear.
“Now we know that zinc is embedded within structures that are absolutely critical for nerve cell activity,” said Choe. “Furthermore, the amino acids that cradle the zinc atoms are completely conserved among the three classes of channels, telling us that during evolution there has been selective pressure to keep that zinc in place.”
All four kinds of Aplysia potassium channels studied by Choe and colleagues have analogs in the human nervous system, so the investigators believe that their studies of zinc’s role in Aplysia channel function are directly relevant to understanding its function in the human brain.
First author of the study, titled “Zn2+-binding and molecular determinants of tetramerization in voltage-gated K+ channels,” is Kathryn Bixby, currently at the University of California, San Diego. Other Salk authors include Andreas Kreusch, a postdoctoral researcher in Choe’s laboratory and Max Nanao, who is also a graduate student at the University of California, San Diego. The study was done in collaboration with N. Vivienne Shen and Paul J. Pffafinger at Baylor College of Medicine and Henry Bellamy at the Stanford Synchroton Radiation Laboratory. The work was supported by the National Institutes of Health and the American Heart Association.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.