Protons power the unmentionable

Source: University of Utah

Muscles usually contract when a neurotransmitter molecule is released from nerve cells onto muscle cells, but University of Utah scientists have discovered that bare subatomic protons can act like larger, more complex neurotransmitters, making gut muscles contract in Caenorhabditis elegans so the nematodes can defecate.

"There are relatively few molecules that serve as neurotransmitters to trigger electrical changes in cells," Professor Erik Jorgensen, scientific director of the Brain Institute at the university and senior author of the study, published in the January 11 issue of the journal Cell, said.

"Protons are the only new members of this group in nearly 20 years."

While conventional neurotransmitters such as serotonin, dopamine and GABA are molecules made of many atoms, the new study revealed a surprise: protons - which are single hydrogen atoms stripped of their electrons - are pumped out of the nematode's gut by one kind of protein and then bind to receptor proteins on neighbouring muscles, making the muscles contract so the worm defecates.

Not only did the researchers show protons can act like neurotransmitters, they identified the genes and proteins involved in the process in C.elegans.

Previous research indicated the brains of humans and mice also have proton pumps and receptors to move protons between cells. The new study raises the possibility those protons may be transmitting nerve signals in the brain, according to Jorgensen and study co-author Wayne Davis, a research assistant professor of biology.

"This is the first time we have found protons acting as transmitters," Davis said. "It could be that these processes occur in humans. There are proton pumps present in intestinal cells and in the brain of humans and mice. Some of the pumps are thought to make acid for the gut to digest food. But why are proton pumps in the brain?"

"Mice lacking the proton receptor cannot learn," Jorgensen said. "It may be that the proton pump and receptor are required for learning," and thus protons may act like neurotransmitters in the brain.

Utah graduate student Asim Beg (now at Columbia University) conducted the study with Jorgensen, Davis, graduate student Paola Nix and postdoctoral researcher Glen Ernstrom.

Other neurotransmitters such as serotonin and dopamine are more than 100 times larger than protons. That makes protons "the world's smallest transmitter," Jorgensen said.

Acids burn because they contain high concentrations of protons, which already were known to help the stomach digest food.

The new study shows that at least in some circumstances, protons also may be used by cells to communicate.

"Normally you think of proton concentration increasing to digest food," Davis said. "Now we see the cell is using these protons to communicate. The protons are acting like a word in a language that cells use to talk to each other."

When the study began, nobody thought a new transmitter would be identified. Instead, the researchers were trying to understand how worms defecate, which in roundworms is surprisingly complex.

The animal has muscle contractions every 50 seconds that result in expulsion of intestinal contents. The 50-second cycle is an example of a biological clock, like those that regulate wake-sleep cycles and many other behaviours in animals.

"We were interested in teasing apart the components required for [defecation] clock function," Nix said. "To do that we searched for mutations that affected the clock."

By exposing worms to chemicals that altered their DNA, the researchers found mutant worms that couldn't defecate or had trouble doing so. "The worms are constantly eating, so if they don't poop regularly, they become very constipated," she said.

In the worm's tail, muscles surround the tube-shaped intestine, and there is a fluid-filled space between the intestine and the surrounding muscles. The muscles contract to help the worm defecate. The researchers identified two different gene mutations that prevented such contractions.

One gene, named pbo-4 (for posterior body contraction), produces a protein that pumps protons out of the intestine, acting "like a revolving door where sodium is allowed in [the gut] while protons go out [of the gut] into the fluid-filled space that is very close to the surrounding muscle," Davis said.

The second gene, pbo-5, makes a receptor protein on the muscles that surround the gut. After the protons are released from the intestine, they bind to the receptor protein.

"The receptor acts like an ear that allows the muscle to hear that protons are present," Beg said. "The receptor opens when the proton binds to it, forming a hole in the muscle cell that allows large numbers of ions like sodium to flow in. The ions make the muscle contract."