The Shape of Things
Ion channels are a class of proteins that control the flow of ions such as calcium, sodium or potassium across the membranes of cells, DeCaen explains. Maintaining a proper flow of ions is critical to a multitude of bodily functions, from the transmission of messages between brain cells to the beating of the heart.
“It seems like a simple job, but it ends up frequently being problematic,” he says.
Mutations in the genes that encode ion channels have been linked to many medical conditions. To understand how these mutations lead to disease, ion channel investigators try to piece together the three-dimensional molecular structures of ion channels.
For example, DeCaen and colleagues from the lab of Erhu Cao, PhD, at the University of Utah took this approach to better understand a gene called polycystic kidney disease 2 (PKD2). Mutations in the gene had been found in patients who develop large cysts in their kidneys that cause organ failure. Scientists knew the gene encoded an ion channel that controls the flow of ions, but did not know which ions. Work from DeCaen’s lab pointed to potassium and sodium.
“We now know what ions move through the channel, but no one had any idea of what it looked like in three-dimensional space,” DeCaen says. “Since function follows form, we figured that this is an important knowledge gap to fill.”
So, the team chilled the protein to a very low temperature and then used a powerful electron microscope to get the first glimpse of the protein’s configuration. The results were published in the journal Cell last year.
“Now that we know what the ion channel looks like, we can see how mutations that cause alterations in its structure may cause it to malfunction in the disease state,” he says. “We can start to do some pie-in-the-sky thinking about developing small molecules that can affect the ion channel’s function.”
For example, in polycystic kidney disease it is not clear whether mutations cause the PKD2 channel to be continually open, allowing an unending flow of ions, or if the mutation closes the channel. There might even be a mix of on/off effects depending on the specific mutation. So, DeCaen and colleagues are using electrophysiological techniques to find out. Their results could inform the design of drugs to combat the disease.
DeCaen has also been consulting Northwestern clinicians about complications beyond cysts in patients with polycystic kidney disease. These clinical insights might provide clues on the function of these ion channels throughout the body and potentially suggest treatment strategies.
“In ion channel research, you need a broad range of expertise in medicine,” DeCaen explained. “You need a neurologist, a cardiac arrhythmias expert and kidney disease experts. We have that large pool of scientists and clinicians here at Northwestern.”
Working with George, and Jennifer Kearney, PhD, associate professor of Pharmacology, DeCaen is also probing the role of ion channels in epilepsy. His lab is recreating the structure of a bacterial version of an epilepsy-linked sodium channel as a first step toward recreating the mammalian version. So far, the work has yielded unexpected clinical benefits.
“This gave us our first glimpse into how anti-epileptic drugs work,” DeCaen says. It has also suggested potential antibacterial treatments that would target the channel.
The applications of this line of research go even further: This summer, George and colleagues showed how mutations in a sodium channel called Nav1.9 can lead to a disorder where people are unable to feel pain. The findings, published in The Journal of Clinical Investigation, might have implications for the development of novel therapies for pain.
“Ion channels represent an under-appreciated class of druggable protein targets,” says George. “A goal for the Department of Pharmacology has been to place ion channels at the center stage of research efforts to find new drug targets.”