Toxic Compound Opens Potentially Important Cell Gates

Scientists from The Johns Hopkins University, Harvard University and The University of Hawaii have reported new evidence rehabilitating the reputation of this biological pariah, known as adenosine diphosphate ribose, or ADP-ribose. They found that as cells work to break the compound down, a pause in the disposal process allows ADP-ribose to open a gate for transporting calcium through cell membranes in the brain, lungs, heart, spleen, liver, kidney, and elsewhere.

"It's important to know what opens and closes calcium channels, because calcium transport into and out of cells is a significant step in a wide variety of physiological processes," says Maurice Bessman, professor of biology in the Krieger School of Arts and Sciences at Hopkins and an author of a paper in the May 31 issue of "Nature." "Examples include nerve cell signaling processes, regulation of the heartbeat and muscle contraction, immune system responses, olfaction, and energy metabolism."

Researchers found evidence that a protein originally used solely to break down ADP-ribose had become fused with a protein that creates a calcium channel known as LTRPC2. A key segment of the disposal protein apparently was incorporated through evolution into the larger protein that creates the calcium channel.

"Two different processes -- two old functions -- have been very tightly tied together, but they're both still carrying out their own individual enzymatic reactions," Bessman says. "You get a whole that is greater than the sum of its parts. We don't think this is the last example of this type of fusion, and will be looking for other similar proteins usurped for other functions in a comparable fashion."

Discovery of the link began when Andrew Scharenberg's lab at Harvard Medical School, which specializes in calcium channels' roles in the immune system, identified two genes that they thought were linked to calcium channels.

Scharenberg noted that both genes contained a section of DNA similar to a DNA segment that is the defining characteristic of a family of genes Bessman's group discovered and calls "Nudix" hydrolases. The characteristic section of these genes is known as a "Nudix box."

"We think this family of genes has been around for a long time," says Christopher Dunn, a research technician at Hopkins and an author on the "Nature" paper. "Although the proteins we worked with in this particular project are from humans, the Nudix hydrolases are found in the most primitive to the highest organisms, with nearly 600 members in 200 species identified so far."