Transistors of the Brain

What started as a year-long sabbatical in New York for Dr. William Zagotta turned into a collaboration that led to new insight on ion channels, tiny gateways that regulate electrical signals in cells.

Zagotta, professor of physiology and biophysics in the UW School of Medicine, went to Columbia University to work with researcher Dr. Eric Gouaux. They combined Zagotta's work on ion channels and Gouaux's expertise in X-ray crystallography, and set out to determine part of the atomic structure of the ion channels studied in Zagotta's UW lab.

Ion channels, found in cells throughout the body, regulate electrical impulses for many physiological activities, from the beat of the human heart to the operation of photoreceptor cells in the eye. Ion channels defects can underlie some genetic disorders, such as cystic fibrosis.

Zagotta's lab studies HCN ion channels, which play a role in heart and neuron functions.

"These ion channels are like the transistors of the brain," Zagotta explained.
HCN channels are regulated proteins that open and close ion-permeable pores in the cell membrane. That repetitive function is controlled by cyclic AMP, a nucleotide that binds to the surface of the HCN protein and switches the ion channel on and off.

Zagotta and Gouaux led a team of researchers from both Columbia University and the UW who looked at the structure of HCN where cAMP, the switch for the ion channel, binds to the protein. They used X-ray crystallography to produce a 3-D model of that part of the HCN channel's atomic structure. The results of their work appeared in the Sept. 11, 2003, issue of the journal Nature.

"Determining the structure allows for future experiments to try to better understand how HCN ion channels open, and how cyclic AMP causes them to open," Zagotta said. "Ultimately, these structures are also the framework for designing drugs to target them."

Knowing more about HCN channels assists in research on another kind of ion channel with a similar structure - CNG channels, which play a role in vision. Having found the 3-D structure of one type of HCN channel will help in determining the structure of the rest of the family of HCN channels, Zagotta said, as well as the different types of CNG channels.