KU researchers uncover mechanics of protein implicated in neurological disorders

Magnesium is an essential mineral in the body. Not only is it important for bone health, energy production, muscle function and blood pressure control, it’s also vital for the function of neurons, nerve cells in the brain and nervous system that transmit electrical and chemical signals throughout the body.

Lejla Zubcevic, Ph.D., assistant professor in the Department of Biochemistry and Molecular Biology at the University of Kansas School of Medicine, is working to learn more about how neurons maintain the ionic balance — regulation of charged particles — that allows them to function properly. Magnesium is one of those ions. Low magnesium plays a role in seizures, coordination, behavior and neuro-muscle development and function.

“The brain seems to be very sensitive to changes in magnesium levels,” Zubcevic said. “And we have all this clinical data that indicates the role of magnesium to be really significant. But we don’t know some very basic things … from the proteins that are involved to the actual mechanisms by which magnesium might be involved in brain function, we really know very little.”

Thanks to research that Zubcevic and her colleagues published recently in Nature Communications, we now know more. This study examines a protein known as NIPA2, which is involved in several neurological disorders. “This protein was one of the proteins believed to transport magnesium ions in the brain, but there was little data to support that presumed function,” she said.

The researchers wanted to look at the protein at its purest, most basic level, so they isolated it from its native environment and then put it in the membrane of a liposome, an artificial cell they constructed and could control. Inside the liposome was a tracer dye, which lit up whenever magnesium entered the liposome via the protein.

And they found that NIPA2 does transport magnesium ions, passively (without help from a driving force, such as a secondary ion), across the cell membrane in this system.

But they also learned something else: that NIPA2 prefers to transport more complex molecules called nucleotides. In fact, in an experiment they conducted using ATP (adenosine triphosphate), a nucleotide crucial to energy production, they found that the NIPA2 protein favored transporting the ATP nucleotide over the magnesium ions.

This finding indicates that magnesium transport likely is not the primary function of NIPA2, and that the NIPA2 protein likely does not transport magnesium in the neurons when nucleotides are present. “The fact that it transports magnesium may be more of an evolutionary coincidence,” Zubcevic noted. “NIPA2 might be part of a larger, nucleotide-based signaling pathway that regulates neuronal function.”

The researchers also studied the structure of the NIPA2 protein by using  KU Medical Center's cryogenic electron microscope, which can reveal the structure of a molecule at nearly atomic resolution, and were able to determine the distinct movements by which the NIPA2 protein carries out transport.

These findings help lay the groundwork for future studies on the role of NIPA2 in disease. “We can now better understand what might be affected or go wrong when this protein malfunctions in disease,” said Zubcevic. “That means that we can better consider treatments. And because we have determined the atomic structure of NIPA2, it'll be easier to develop drugs to target it.”