[tt] proton-powered pooping

[Eugen Leitl]

(H+ as neurotransmitter, that's some fancy-ass shit)

http://www.unews.utah.edu/p/?r=112707-3

Proton Powered Pooping

Discovery: Subatomic Protons Act like Nerve-Signal Transmitters

Media Contacts

Jan. 10, 2008 - Muscles usually contract when a neurotransmitter molecule is
released from nerve cells onto muscle cells. But University of Utah
scientists discovered that bare subatomic protons can act like larger, more
complex neurotransmitters, making gut muscles contract in tiny round worms so
the worms can poop.

"There are relatively few molecules that serve as neurotransmitters to
trigger electrical changes in cells. Protons are the only new members of this
group in nearly 20 years," says biology Professor Erik Jorgensen, scientific
director of the Brain Institute at the University of Utah and senior author
of the study in the Jan. 11 issue of the journal Cell.

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 a round worm's gut by one kind of protein and then bind to receptor
proteins on neighboring 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 round
worms, which are about 1 millimeter (a 25th of an inch) long and also are
known as nematodes.

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,
says 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
says. "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?"

Jorgensen adds: "Mice lacking the proton receptor cannot learn. 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.  

A Discovery from Constipated Worms

Atoms are made of nuclei that contain positively charged protons and
uncharged neutrons, orbited by negatively charged electrons. So protons are
among the smallest components of matter.

Previously recognized neurotransmitters such as serotonin (known for its role
in preventing depression) and dopamine (involved in addiction to cocaine and
other drugs) are more than 100 times larger than protons. That makes protons
"the world's smallest transmitter," says Jorgensen, also a Howard Hughes
Medical Institute investigator.   

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 says. "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 poop. Why?
"Eating, moving, having sex and pooping are common things that all animals
do," says Davis. 

Nematodes, or Caenorhabditis elegans, have about 1,000 cells and are simple
animals studied by researchers worldwide. Nematodes have many of the same
tissues - nerves, muscle and intestine - that are found in humans, and most
of the same genes, making the worm a model for studying human biology.  

Defecation in round worms 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 behaviors in animals.

"We were interested in teasing apart the components required for [defecation]
clock function," says Nix. "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," says Nix.

In the round 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.

Proteins and Protons Propel Pooping Process 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," says Davis.

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," says Beg. 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.

The researchers knew protons were being released from the gut because they
could see their effects through a microscope.

They bred worms with a green fluorescent protein that loses it color when
many protons are present. The adult worms had the green protein in the
fluid-filled space between the intestine and the surrounding muscle - a space
that Ernstrom says "is approximately 1,000 times smaller than the width of a
hair."

The scientists were able to show protons were pumped from the intestinal wall
and to the surrounding muscle because, under a microscope, the fluid-filled
space became less green. In mutant worms lacking the proton pump, the green
remained unchanged, showing that protons were not released from the gut into
the space.

In the next experiment, the researchers added protons to the fluid-filled
space between the intestine and surrounding muscle in the mutants lacking the
proton pump. The added protons made the muscle contract. That indicated
protons indeed were acting like a neurotransmitter to carry the signal for
contraction from the intestine to the surrounding muscle.

"To prove that it is the protons triggering the contraction, we want to
supply the protons ourselves," says Davis. "A fine needle filled with protons
was used to inject protons in the space between the muscle and gut. We can
bypass the gut and fool the muscle into thinking the gut is releasing
protons, and the muscle contracts."

The study was funded by the National Institutes of Health and the Howard
Hughes Medical Institute.