Scientists from The Scripps Research Institute have identified a surprising new molecular pathway in skin cells that is involved in wound-healing and sensory communication.
The new study, published in Nature Communications on June 28, 2011, shows that in this process skin cells produce nitric oxide, a versatile signaling molecule involved in temperature-sensing and wound-healing. This alternative, oxygen-independent mode of nitric oxide production previously had been thought to occur only outside cells.
"This alternative nitric oxide production process could prove to be crucial in the clinic," said Ardem Patapoutian, a professor at the Dorris Neuroscience Center at Scripps Research and the senior author of the study. "The usual nitric oxide production process requires oxygen, so drugs that target that process might not work when oxygen availability is low after blood supply disruption."
Studying the Biology of Sensation
Patapoutian's lab focuses on the molecular biology of skin-based sensory pathways—pathways that typically start with stimulus-sensing receptors on nerve ends. Such receptors include the TRPV (transient receptor potential vanilloid) class of receptors, which are sensitive to various temperature- and pain-related stimuli. One of these receptors, TRPV3, is found not only on some nerve cells and nerve ends, but also on outer skin cells known as keratinocytes.
In 2005, Patapoutian's lab reported in the journal Science that TRPV3 seemed to be a heat-sensing receptor; mice bred without it lacked a normal sensitivity to moderately warm stimuli. "That and previous findings made us suspect that TRPV3-expressing keratinocytes are somehow involved in sending thermosensory signals to local nerve ends," said Patapoutian.
In the current study, Patapoutian, his graduate student Takashi Miyamoto, and their colleagues demonstrated that TRPV3 activation leads to the production of nitric oxide in keratinocytes—which suggests that nitric oxide is the carrier of thermosensory signals from skin cells to nearby nerve ends. A simple gas consisting of one atom of nitrogen bound to one atom of oxygen, nitric oxide is one of the more evolutionarily ancient biological signaling molecules, and even plays a role as a neurotransmitter in the brain.
"Nitric oxide was high on our list of possibilities because it is known to be produced in keratinocytes when they are warmed," said Miyamoto, who was first author of the study.
A Surprising Result
Miyamoto applied compounds that are known activators of TRPV3 to cultured mouse keratinocytes, and observed that the cells sharply increased their production of nitric oxide.
"The surprise was that I couldn't find evidence that the nitric oxide was being produced in the normal way, with nitric oxide synthase (NOS) enzymes," he said. The keratinocytes turned out to be producing nitric oxide through a different process, which is known to occur in saliva and other bodily fluids, but hadn't yet been seen in cells.
This alternative nitric oxide production occurs by the stripping of oxygen atoms from compounds called nitrites, which normally come from dietary sources. When Miyamoto deprived the cultured cells of nitrites, their TRPV3-triggered production of nitric oxide dropped to near zero.
To confirm the role of nitrites in this pathway, Miyamoto compared the mice bred without TRPV3—which don't distinguish two different innocuous warm temperatures—to those with no-nitrite diets. "The behavior of the no-nitrite mice was basically the same as that of the TRPV3-knockout mice," he said. Feeding TRPV3-knockout mice with no-nitrite diets had no additive effect, which again suggested that the two work on the same pathway.
Next, the scientists asked, "If nitric oxide is a messenger that delivers temperature-sense signals from skin cells to nearby nerve ends, then to what nerve-end receptor does it bind?" Miyamoto, Patapoutian, and their colleagues suspected TRPV1, a known pain and temperature sensor on nerve ends, which their lab had shown to be activated by nitric oxide, in a study published in 2009. In the present study, they used a chemical to block the activity of TRPV1 receptors in mice, and observed that the lack of TRPV3 or nitrites no longer made a difference in the animal's behavior—a result consistent with the idea that TRPV1 is the main nerve-end receptor on this thermosensory pathway, acting directly or indirectly.
Hints of Things to Come
Nitric oxide's versatility as a signaling molecule also led the researchers to look for other processes in which the TRPV3-mediated pathway might be involved. "We found evidence that the nitric oxide produced by this pathway makes a partial contribution to wound-healing and also specifically to the keratinocyte migration that occurs during wound healing," said Miyamoto.
The team now plans to detail the elements of the TRPV3-activated nitric oxide pathway in temperature sensing, and to look for evidence that the same kind of nitrite-dependent pathway is involved in other nitric oxide-producing cells throughout the body.
"The dogma has been that nitric oxide can be produced in cells only with NOS enzymes, but this study hints that nitrite-based nitric oxide production could potentially be just as important," Miyamoto said.
In addition to Patapoutian and Miyamoto, other co-authors of the study, "TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin," were Matt J. Petrus and Adrienne E. Dubin, also of the Patapoutian lab at Scripps Research. For more information, see http://www.nature.com/ncomms/journal/v2/n6/abs/ncomms1371.html
Funding for the study was provided by the National Institutes of Health, Novartis Research Foundation, and the Skaggs Institute for Chemical Biology at Scripps Research.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see www.scripps.edu .
Mika Ono | EurekAlert!
Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg
The balancing act: An enzyme that links endocytosis to membrane recycling
07.12.2016 | National Centre for Biological Sciences
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
08.12.2016 | Physics and Astronomy
08.12.2016 | Health and Medicine
08.12.2016 | Life Sciences