Pharmacology

Live or die? Postdoc Shepherd researches factors affecting cell life and death

Andrew Shepherd sees basic scientific research as something special on the path toward scientific discovery.

“To begin to fit all the pieces of the puzzle together, a lot of basic research like ours must happen first,” says Shepherd, a postdoctoral scholar in the Department of Pharmacology in the University of Iowa’s Carver College of Medicine. “I consider our lab fortunate that we were able to take these existing ideas and observations and fit them into a clinically relevant context. That’s the single most exciting aspect about basic research to me.”

Shepherd’s most recent research endeavor involved uncovering a mechanism underlying the regulation of neuronal excitability, survival, and death—processes central to such diseases as epilepsy, neuro-HIV, and stroke.

In a study published in the Journal of Neuroscience in December, Shepherd and his colleagues examined the release of a cell-signaling protein molecule, an inflammatory mediator called SDF-1alpha. Certain disease states prompt an abnormal release of SDF-1alpha molecules, which send signals telling cells to open the flood gates that control aspects of cellular voltage flow.

 

Kv2.1’s role in cell death

In such cases, Kv2.1 is over-activated. Kv2.1 is a protein that holds the key to opening voltage-gated potassium channels. These channels regulate many body functions, including neurotransmitter release, heart rate, insulin secretion, neuronal excitability, electrolyte transport, smooth muscle contraction, and cell volume.

In healthy cells, the right amount of potassium helps maintain cell function. When the balance of potassium is disturbed, cell death may occur.

“In the acute phase, such over-activation of Kv2.1 is a good thing. It seems to be keeping the neurons alive when they otherwise would die from overwhelming stimulation,” says Shepherd, first author of the study. “What seems to go wrong is over-activation of this potassium channel, which persists for several hours and initiates cell death. The cells keep on losing potassium to the point where they can no longer function properly.”

Shepherd and his colleagues observed this change in neuronal excitability and cell death in rat hippocampal neurons due to modifications in this potassium channel. But how is the over-activation of Kv2.1 causing cell death?

“We think that the sustained loss of potassium from the cell compromises its ability to generate energy,” says Shepherd, who earned his Ph.D. in life sciences from the University of Manchester (England). “If your cell’s power producers aren’t functioning well anymore because of a lack of potassium, the cell can’t generate the required energy to survive. In order to function normally, neurons need that energy to keep lots of potassium inside with very little potassium outside.”

The Kv2.1 channel plays a central role, both in keeping neurons alive during altered cellular excitability and in letting potassium flow out of the neurons, which causes cell death.

“These research findings are highly significant to our basic understanding of the precise regulation of neuronal excitability and survival-death dynamics of mammalian brain neurons under a variety of neuropathological conditions,” says D.P. Mohapatra , principal investigator of this study, assistant professor in pharmacology and anesthesia, and faculty member in the Interdisciplinary Graduate Program in Neuroscience.

Mohapatra adds that Shepherd’s well-planned experiments and careful analysis of results led to this important research finding, which could be key in designing a strategy for treating multiple neurological disease conditions in the future.

This work was funded by the UI Office of the Vice President for Research, an Epilepsy Foundation and American Epilepsy Society Research Grant, and a National Institutes of Health/National Institute of Neurological Disorders and Stroke Grant.

 

Shepherd’s academic journey

Shepherd has grown as a scientist since joining Mohapatra’s laboratory in 2008.

“I’ve gained valuable insight into what setting up your own lab and research projects entails, rather than being ‘parachuted’ into an established lab and established projects,” Shepherd says. “It’s an experience that a lot of postdocs don’t necessarily get, and it wasn’t without moments of pressure and doubt, but I feel like that effort that we all made in those early years is now starting to bear fruit.”

The University of Iowa has been a great place for Shepherd to work.

“The fact that the Carver College of Medicine is so closely associated with the UI Hospitals and Clinics is a great advantage for researchers like us,” says Shepherd, whose appointment at the UI will end in 2014. “It’s invaluable in creating the kind of collaborative environment and translational projects that are vital for coming up with new ideas and making important discoveries.”

Shepherd became interested in basic research as an undergraduate at the University of Manchester (England).

“I always remember being particularly interested in those lecture topics that had a clear, direct relevance to human diseases, and what we could do to further our understanding and eventually develop improved treatments,” Shepherd says. “Sadly, I think all of us are familiar in one way or another with at least one person afflicted with a debilitating neurodegenerative condition.”

As featured in IowaNow (http://now.uiowa.edu/2013/05/live-or-die)