Team lays groundwork for developing treatment of cardiac disorder

Four graduate students and a postdoctoral researcher pose with equipment they use to conduct research

Members of professor Gary Lorigan’s research team include (from left to right): graduate student Andrew Craig, postdoctoral researcher Dr. Indra Dev Sahu, and graduate students Lauren Bottorf, Dan Drew and Afu Zhang. Not pictured are graduate student Lishan Liu and undergraduate students Megan Dunagan, Raven Comer, Kunkun Wang, and Avnika Bali.

 

“Scared to death,” is more than a hyperbolic phrase to sufferers of long QT syndrome (LQTS); it’s a very real possibility. In LQTS, exercise and unexpected noise – like the ring of a doorbell or the backfire of a car engine – can set off potentially fatal heart arrhythmias in otherwise healthy children, teenagers, and young adults. It may even be a cause of sudden infant death syndrome (SIDS).

Most cases of LQTS are the result of inherited genetic mutations. But while scientists have identified a number of genes associated with LQTS, the mechanism by which mutations in these genes affect the electrical system that controls the heart’s rhythm is not well understood. As a result, the development of medical treatments for the disorder has been limited.

Gary Lorigan wants to change that. A professor in Miami’s Department of Chemistry & Biochemistry, Lorigan is working to describe the structural and dynamic properties of proteins produced by two genes implicated in LQTS: KCNE1 and KCNQ1.

Together, the KCNE1 and KCNQ1 proteins control the electrical potential of a cardiac cell by managing the flow of positively charged potassium ions across the cell’s membrane. “We know that the protein produced by KCNE1 binds to the protein produced by KCNQ1 to regulate the flow of potassium, but we don’t know how it binds or where it binds,” says Lorigan. “We know that mutations cause differences in this binding, but we don’t know why.”

In an effort to answer these questions, Lorigan and his colleagues – including a post-doctoral fellow, five graduate students, and seven undergraduate students – are using nuclear magnetic resonance (NMR) and an advanced electron paramagnetic resonance (EPR) technique known as double electron-electron resonance (DEER) to analyze how the KCNE1 and KCNQ1 proteins are built, how they move around, and how they bind.

In DEER, special molecules are used to tag specific regions within a protein or other macromolecule. Lorigan and his team use these so-called spin labels to measure distances within the KCNE1 and KCNQ1 proteins. “That’s how we’re actually able to visualize their structure,” he says.

One year into a project funded with $1.1 million from the National Institutes of Health (NIH), Lorigan’s team has managed to define the structure of the KNCE1 protein in the cell membrane. “That was our goal for the first year,” he says. “We just submitted the paper on that.”

The ultimate goal of the four-year project, according to Lorigan, is to “get structural information and relate that to function.”  Once that fundamental work is complete, the Lorigan team will have paved the way for translational scientists to begin developing new treatments for patients with LQTS and, potentially, other forms of arrhythmia as well.

Written by Heather Beattey Johnston, Associate Director & Information Coordinator, Office for the Advancement of Research & Scholarship, Miami University

Illustration by Pleiotrope (own work) [Public domain], via Wikimedia Commons. Photo courtesy of Gary Lorigan.

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