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Discovering New Functions in Neuronal Cell Biology, a Step Forward in Understanding Stroke Response and Treatment

When researchers are able to zero in on the smallest physiological interactions, a focused understanding of cellular function during both health and disease begins to take shape. In Dr. Michael Tamkun’s lab, even the smallest changes in molecular function enhance our understanding of neuro-protective response to stroke or epilepsy, and pave the way for more effective treatments in the future. Tamkun’s current research explores the function of ion channels in neurons and their role in the neuro-protective response to stroke or epilepsy.

“We’re interested in the roles of ion channels when they aren’t being ion channels,” said Dr. Michael Tamkun, professor in the Department of Biomedical Sciences. “We believe we’ve discovered that one of these new roles for a particular potassium ion channel is a structural one where it interacts with the endoplasmic reticulum (ER) membrane of the cell.”

Ion channels are pores in the cell’s membrane that gate and control the flow of ions in and out of the cell. Ion flow is critical because it creates the electrical charge underlying communication in the nervous system, heart and muscle contraction,  regulatory signaling, hormone secretion, and electrolyte regulation.

Dr. Tamkun and his colleagues are focusing specifically in the microanatomy of nerve cells. Through utilization of single channel tracking methodologies (also pioneered by Dr. Tamkun), he has discovered clusters of voltage-gated ion channels that have aggregated on the cell surface, but are not actively serving as gatekeepers for ion flow in and out of the neuron. Instead, they are forming spot welds between the cell plasma membrane and the intracellular ER membrane.

“You need a lot of these ion channel proteins to form these spot welds, but if nature hadn’t figured out how to turn these channels off – meaning they were still conducting ions – flux activity would be so high that it would turn neurons off entirely,” said Tamkun. “Evolution had to figure out how to turn them off, but previously we couldn’t understand why – now we do.”

Tamkun discovered that these junctions play a membrane trafficking role. They are hubs for how proteins get to and from the cell surface. These junctions are so highly sensitive to stroke or seizures that they fall apart when an episode occurs.

“The next basic question is do we want to make stroke treatments that maintain these channels clusters in the ER membrane or enhance the dispersal,” said Tamkun. “We don’t know if the stroke response is a good or a bad thing – is it the neuron’s attempt to save itself or is this one of the side effects of stroke that damage the cell?”

Dr. Tamkun’s research has evolved out of his years spent developing high resolution imaging techniques that can follow the movement and diffusion of single molecules in real time through a cell. Since that time, these single molecule interests have led to the study of macromolecular complexes that involve collaborations with three other leading institutions – the University of Illinois, University of Colorado School of Medicine, and the University of New Mexico Department of Physics.

“Our discovery of the role of this ion channel to restructure the ER membrane represents a new area of cell biology – it illustrates how little we really know about how a cell works,” said Tamkun. “The long-term goal is to build a deeper understanding of nerve cell biology so we know how to modulate things when developing pharmaceuticals and treatments for debilitating neurological conditions and disease.”