Vitamin C keeps neurons healthy
Our brains soak up vitamin C (ascorbate), but what this anti-oxidant chemical is doing in the nervous system has remained unclear. James May, M.D., and colleagues report in the Feb. 15 Early View of the Journal of Neuroscience Research that maintenance of intracellular ascorbate is crucial for neuronal development, functional maturation and antioxidant responses.
Neurons rely on the sodium-dependent vitamin C transporter, SVCT2, to accumulate high intracellular levels of ascorbate — more than 100 times the plasma ascorbate concentration. Mice lacking the gene for SVCT2 die within minutes after birth, preventing whole-animal studies of the role of SVCT2 during postnatal neuronal development. To probe whether SVCT2 activity is required for normal neuronal development, May and colleagues isolated hippocampal neurons from embryonic mice with or without SVCT2, and studied these neurons in vitro.
Neurons lacking SVCT2 had significantly reduced spontaneous electrical activity and stunted growth: there were fewer dendritic branches and reduced dendritic lengths. The number of excitatory glutamate receptor clusters was also reduced, consistent with deranged neuronal activity in the absence of ascorbate. The presence of SVCT2 in wild-type neurons protected the cells from death resulting from hydrogen peroxide (oxidative injury) and from NMDA (excitotoxicity), compared to cells lacking SVCT2.
— Leigh MacMillan
How selenoproteins deliver the goods
Nuts, cereals, meat, fish and eggs supply the body with selenium, an essential trace element required for the proper function of many enzymes, antioxidant responses and sperm production. But how the proteins that transport selenium, called selenoproteins, deliver the nutrient to the body's tissues has puzzled researchers.
Previously, Raymond Burk, M.D., and colleagues found that mice lacking selenoprotein P were infertile and develop progressive neurological disease. Burk's team has now identified a specific region of selenoprotein P — the C-terminal domain — as a key factor in its ability to deliver selenium to the brain and testes.
In the Journal of Biological Chemistry, the researchers report that mice with deletions of this region had decreased levels of selenium in brain and testes — similar to selenoprotein P knockout mice — but maintained whole-body selenium better than knockout mice. Additionally, mice lacking the C-terminal domain developed progressive neurological disease and had defective sperm and impaired fertility even when fed a high-selenium diet.
In a separate paper in the same journal, Gary Olson, Ph.D., in collaboration with Burk and colleagues, further delineated the selenium uptake mechanism in testes, identifying the apolipoprotein E receptor 2 as the receptor for selenoprotein P in the mouse testis.
Together, the studies suggest mechanisms that help maintain selenium levels in the brain and testes, which may play important roles in neurological disorders and male infertility.
— Melissa Marino
Preventing drug-induced arrhythmias
Half of all drugs withdrawn from the U.S. market since 1998 were removed because they block a potassium channel called HERG. In some individuals, the unintended block of HERG causes “acquired long QT syndrome,” a change in the heart's electrical signaling that can lead to potentially fatal arrhythmias. Not everyone who takes a HERG-blocking drug suffers the adverse reaction, prompting investigators to search for the factors that influence a person's response to HERG-blocking drugs.
Sabina Kupershmidt, Ph.D., and colleagues have characterized one such factor, a protein called KCR1. They previously showed in cardiac cells grown in the laboratory that KCR1 prevents certain drugs from blocking the HERG channel. The investigators now report that KCR1 is an alpha-1,2-glucosyltransferase, an enzyme that participates in the cellular glycosylation pathways that add sugar molecules to proteins. The discovery came from KCR1's homology to a yeast alpha-glucosyltransferase called ALG10. Like KCR1, ALG10 “protects” HERG from drug block, the researchers found.
The mechanism for KCR1 protection against HERG block was surprising, the researchers wrote in the Feb. 23 issue of the Journal of Biological Chemistry. The findings suggest that the overall status of cellular glycosylation may be a risk factor for acquired long QT syndrome and open a new avenue for preventing the syndrome.
— Leigh MacMillan
We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.
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