SCIENCE & TECHNOLOGY
MORE THAN JUST PORES
ADAPTED FROM SCIENCE
tion. Subsequent studies showed that ion channels form complexes with kinases. However, “it was always thought that the ion channel itself was the passive endpoint of signaling regulation,” Kaczmarek says. At the Biophysical Society meeting, two researchers delivered Kaczmarek’s punch ION CHANNELS can also act as enzymes and communication links line, discussing how two different classes CARMEN DRAHL, C&EN WASHINGTON of ion channels can themselves act as kinases. Symposium chair Federico Sesti, a biophysicist at the University of Medicine Kaczmarek of Yale University, who did & Dentistry of New Jersey, in Piscataway, AS IF ION CHANNELS weren’t doing not attend the symposium, the idea that described a kinase that is part of a voltenough on their own—underpinning nerve ion channels could influence biochemiage-gated potassium ion (K+) channel in impulses and muscle contraction— cal pathways in the cell is “the big punch researchers are now finding that they can worms. University of Pennsylvania School line” in the story of ion channel research. do even more as team players in the cell. of Medicine neuroscientist Irwin B. LeviIn the 1970s and ’80s, it became clear that Voltage-gated ion channels are memtan reported a similar kinase in flies that ion channels could be regulated by biobrane pores that sense changes in local is associated with a K+ channel that opens chemical pathways, he says. For example, charge distribution across membranes. and closes in response to both voltage and investigations showed that channels act as They open and close in response, ushercalcium concentration. substrates for kinases, enzymes that reguing ions into and out of cells to propagate Voltage-gated K+ channels help nerve late biological processes by phosphorylaelectrical signals. Such channels were once cell membranes return to their resting thought to be lonely thoroughfares. state after a nerve impulse. Their biBut a symposium at the 52nd Bioological activity is fine-tuned by regPOLICING THE GATE physical Society Annual Meeting and ulatory β-subunits, proteins tightly This voltage-gated potassium ion channel (blue) 16th International Biophysics Conassociated with the channel. Sesti’s has four oxidoreductase subunits (orange), each gress, held last month in Long Beach, kinase is a K+ channel β-subunit, with an NADPH cofactor (green). This structure Calif., brought attention to these and in vitro it phosphorylates the K+ is guiding efforts to understand how the flow of proteins’ other roles. channel to which it is attached. That potassium ions (magenta) through the pore is “Today, I’d like to challenge you action appears to affect current flow coupled to oxidoreductase activity. to think about voltage-gated ion through the pore. channels in a different way,” said Sesti’s latest results indicate that University of Michigan, Ann Arbor, the kinase subunits affect habitpharmacologist Lori L. Isom, setbased learning in worms. “This type ting the tone for the “Non-Conductof learning allows you to filter inforing Functions of Ion Channels” mation,” Sesti said. symposium. Isom and three other Usually, worms are sensitive to speakers presented evidence that touch and will recoil from a tap to ion channels do other things besides their bodies, Sesti explained. Evengatekeeping: They can participate in tually, they habituate to repeated cell-cell interactions and they can poking. He observed this response catalyze reactions. for normal worms, but mutant The biological consequences of worms with a defective kinase didn’t the ion channels’ other jobs are not get used to the poking nearly as yet completely clear. But they may quickly. However, it’s too early to be vital for diseases such as cardiac apply Sesti’s findings to learning disarrhythmia, ataxia, and some types of abilities in people because scientists epilepsy, which may be connected to have yet to find similar β-subunits in ion channel defects but not necessarmore advanced animals. ily to changes in current flow. “There are about 50 inherited disNOT EVERY channel β-subunit is orders of ion channels, and we want a kinase. Structural and functional to understand them genetically and work by several groups suggests that tease out their molecular mechaβ-subunits in voltage-gated K+ channisms,” said symposium attendee nels act as oxidoreductases and even Alfred L. George, chief of Vanderbilt hint that ion flow through the pores University Medical School’s Division is coupled to the enzymes’ activity. of Genetic Medicine and an expert For example, Columbia Univeron mutations of human ion channels. sity structural biologist Ming Zhou For neurochemist Leonard K. and coworkers recently confirmed WWW.C E N- ONLI NE .ORG
34
M ARC H 3, 20 0 8
SCIENCE & TECHNOLOGY
“The wave of the future is to learn how ion channels function in a cell with lots of other receptors and channels around.” that these β-subunits catalyze an oxidation/reduction reaction. Zhou discussed this work at the meeting. His team found that the β-subunits catalyze the reduction of aldehydes to alcohols, simultaneously oxidizing an NADPH cofactor to NADP+. In addition, Zhou and coworkers have shown that the β-subunits’ enzymatic activity increases current flow through the K+ channel in vitro. Inducing cofactor turnover by adding an oxidant such as hydrogen peroxide rather than adding an aldehyde substrate also increases current flow. “All you need to do is oxidize the NADPH cofactor on the protein to modulate channel activity,” Zhou said. He is currently working toward understanding the structural basis of changes in current flow. A high-resolution structure of the β-subunit together with an entire channel was recently determined by Roderick MacKinnon’s team at Rockefeller University and
is providing a framework for these efforts. β-Subunits are profoundly important not only to the K+ channels but also for their counterpart, the voltage-gated sodium ion (Na+) channel, Michigan’s Isom pointed out. Na+ channels open and let sodium ions rush into nerve cells, making the insides more positive. Knockout mice lacking a specific type of Na+ channel β-subunit, Isom said, resemble the mouse model for pediatric epilepsy and have defects in nerve growth and development. This may be because Na+ channel β-subunits serve as communication links during development. β-Subunits mediate cell adhesion, resulting in their interactions with kinases that are necessary for the sprouting of outgrowths from developing nerve cell bodies. “β-Subunits act as the glue to [stick] specialized signaling molecules to the channel pore,” Isom explained. Other groups have shown that some
Biochemistry – published since 1962
More than chemistry. When it comes to biochemistry and chemical biology, ACS leads the way. Contribute, publish, and review with the journals of the American Chemical Society.
WWW.C E N- ONLI NE .ORG
35
M ARC H 3, 20 0 8
people with inherited epilepsy have mutations in Na+ channel β-subunits. Isom’s team has shown that at least one of these mutations disrupts β-subunit-mediated cell adhesion. This finding could mean that loss of cell-cell communication is important in the development of the disease. The field is far from finding cures for epilepsy or any other disease. But as neuroscientist and symposium attendee Diane Papazian of the University of California, Los Angeles, commented, understanding how ion channels can communicate with their surroundings is an important research direction. “In the last 20 years we were focused on how channels work and how that relates to structure,” she said. “We know a lot about this, particularly in the K+ channel field, but the wave of the future is to learn how they function in a cell with lots of other receptors and channels around—what they do in biology.” ■
ACS Chemical Biology – published since 2006
