Worm defecation holds clues to widespread cell-to-cell communication process

In 2002, researchers won the Nobel Prize for Medicine for work in the roundworm Caenorhabditis elegans (C. elegans) on the genetics of how cells “decide” to self-destruct, a topic now central to human cancer research. Another team won in 2006 for the discovery in C. elegans of an ancient defense mechanism against attempts by viruses to disrupt cells’ genetic machinery.

In the latest worm-related news, today’s publication provides evidence of a new mechanism through which cells in the worm’s intestine signal for nearby muscle cells to flex by briefly making the area between them more acidic. Researchers believe that short-lived changes in acidity may have implications for cell signaling throughout the animal kingdom, from the sending of human nerve messages to worm defecation. The worm’s influence proceeds from the fact that its cells resemble human cells in many ways, but are easier to study.

“I worked with mammals during my training, but my research is focused now exclusively in worms,” said Keith Nehrke, Ph.D., assistant professor of Medicine within the Nephrology Division at the University of Rochester Medical Center, and corresponding author of the Current Biology study. “We don’t restrain or anesthetize the worms during our experiments, which allows us to study complex interactions between organs that only occur in eating, moving animals. It remains to be seen whether pH signaling is commonly utilized in man, but the potential impact is fantastic, as almost all biologic processes are regulated by acidity.”

Theory holds that atoms are the building blocks of the universe. Atoms, in turn, are thought to be composed of energy bundles called electrons that orbit around protons and neutrons at the atom’s center. Furthermore, atoms exhibit a property called charge that explains their behavior. Like charges repel each other; opposites attract, and cells have harnessed these forces to drive life processes.

Some cellular machines work by pumping positively charged particles (e.g. calcium, sodium and potassium ions) into or out of cells. In some cases particles of like charge build up outside the cell, and are eager to rush back in if given the chance. That chance comes, under careful regulation, when cells open channel proteins in their outer membranes, enabling say calcium ions to enter. The charge flow is used as an energy source in some instances, and in others, as a biological switch to kick on life processes. Past studies have shown that the rhythmic wave of muscle contractions that push waste along the worm intestine is carefully regulated by signals captured in rising and falling levels of positively charged calcium ions.

What the current study found is that intertwined with calcium signaling may be a second mechanism, where positively charged hydrogen ions, also called protons, are employed to send signals.

A substance that by nature donates protons to a solution or other molecules is called an acid, and pH is a measure of proton concentration in a fluid. Outside a certain pH range, the proteins that make up human cells and tissues break down and the body fails. One reason that the current work is so intriguing is proteins involved in worm muscle signaling are the same ones recognized for many years as those in charge of maintaining pH balance, a basic housekeeping function. The results of the current work suggest that cells may have usurped this housekeeping function to better communicate.

Nehrke’s Current Biology publication dovetails on an article (Cell 2008, 132, 149) published in January by Eric Jorgensen, Ph.D., professor of Biology at the University of Utah. Jorgensen used a genetic approach to define a signaling link between two specific proteins, a sodium-proton exchanger that pushes protons out of the worm intestine and a proton receptor on adjacent muscle cells that responds to protons by causing muscular contractions that make possible defecation.

The current study validated these conclusions, and demonstrated that protons move from the lumen of the intestine and across the cell prior to signaling adjacent muscles, resulting in pH oscillations inside as well as outside the cells. Sodium/proton exchangers enable the flow of protons across cell membranes while maintaining charge balance. Although this class of proteins has been recognized for many years as capable of helping cells regulate pH and fluid levels, this is the first example of sodium/proton exchangers being involved in communication.

The team used molecular biology techniques to genetically express in the nematode intestinal cells a fluorescent molecule whose brightness is sensitive to pH. Fluorescent imaging then showed proton levels to be carefully controlled during defecation, oscillating in tandem with calcium levels in the intestine. Many calcium regulatory processes are sensitive to pH, and the study suggests that crosstalk occurs between these two signaling mechanisms to regulate the frequency as well as the execution of the defecation muscle contractions.

If this is confirmed in humans, proton signaling could conceivably represent a new target for regulating cell communication, perhaps with therapeutic implications. Many regions in the human body are subject to an acidic environment, and in some cases, are already known to recognize pH changes in their surroundings. In addition, several of proteins that contribute to synaptic transmission, signaling between nerve cells, can be regulated by pH. Are there cellular proton depots near synaptic junctions, with proteins in place to export them as part of signaling mechanisms, and nearby proton receptors awaiting their call? Does abnormal proton signaling contribute to Parkinson’s, Alzheimer’s or other neurodegenerative diseases? Future studies will tell.

Source: University of Rochester

Biosensor for measuring stress in cells
Cancer, nervous system disorders such as Parkinson’s disease, cardiovascular disorders and old age have one thing in common: Both in afflicted tissue and in aging cells, scientists have observed oxidative changes in important biomolecules. These are caused by reactive oxygen molecules, including the notorious “free radicals” that are formed as a by-product of cellular respiration and attack cellular proteins, nucleic and fatty acids.
Novel enzyme inhibitor paves way for new cancer drug
Combining natural organic atoms with metal complexes, scientists at The Wistar Institute have developed a new type of enzyme inhibitor capable of blocking a biochemical pathway that plays a key role in cancer development.
New research tracks effects of addictive drugs on brain
Mount Sinai researchers may have unlocked the key to better understanding the effect addictive drugs have on the human brain. Researchers have just published the new breakthrough study, “Design Logic of a Cannabinoid Receptor Signaling Network that Triggers Neurite Outgrowth,” in the latest issue of Science on May 16th, 2008.
Fuel cells: distant dream, but burning with promise
Some day, fuel cells may power your car and exhaust only water and perhaps carbon dioxide. More efficient and cleaner than an internal combustion engine, their emissions will be much lower. They may also run your home without the energy loss of power lines, or even power your laptop or cell phone. But not today or even tomorrow.
Vitamin D protects cells from stress that can lead to cancer
By inducing a specific gene to increase expression of a key enzyme, vitamin D protects healthy prostate cells from the damage and injuries that can lead to cancer, University of Rochester Medical Center researchers report.
Novel mechanisms controlling insulin release and fat deposition discovered
Scientists at the Swedish medical university Karolinska Institutet have in two recent studies shown that a receptor called ALK7 plays important roles in the regulation of body fat deposition as well as the release of insulin from beta-cells in the pancreas. These findings have implications for the development of treatments against diabetes and obesity.
New study shows how T cell's machinery dials down autoimmunity
A St. Jude Children’s Research Hospital study shows that T cells, the body’s master immune regulators, do not use simple on/off switches to govern the cellular machinery that regulates their development and function. Rather, they possess sophisticated molecular controls that enable them to adjust their function with exquisite precision. Such subtle adjustment enables T cells to modulate their development and function, including avoiding autoimmunity.
Warming up for Magnetic Resonance Imaging
Standard magnetic resonance imaging, MRI, is a superb diagnostic tool but one that suffers from low sensitivity, requiring patients to remain motionless for long periods of time inside noisy, claustrophobic machines. A promising new MRI method, much faster, more selective — able to distinguish even among specific target molecules — and many thousands of times more sensitive, has now been developed in the laboratory by researchers at the Department of Energy's Lawrence Berkeley National Laboratory and the University of California at Berkeley.

Worm defecation holds clues to widespread cell-to-cell communication process

Related stories:

News discussion: