SURPRISING NEW ROLE FOR CALCIUM IN SENSING PAIN
Flow through pain-sensing molecule helps worms adapt to pain
From FMS Global News Desk of Jeanne Hambleton Source Duke University Aug.29 2014, National Science Foundation. News from the Field.
A consensus shape for the calcium ion channel in the worm’s pain receptor nerve that was reached by computer modeling. Credit – Damian van Rossum and Andriy Anishkin, Duke University
A narrated video showing aversive behavior in a worm and a ribbon diagram animation of the ion channel will go live on YouTube on Sept. 2. The Role of Calcium in Pain Signalling – https://www. youtube.com/watch?v=ncxsCcNO-ec ) with Dr. Liedtke.
Durham, NC – When you accidentally touch a hot oven, you rapidly pull your hand away. Although scientists know the basic neural circuits involved in sensing and responding to such painful stimuli, they are still sorting out the molecular players.
Duke researchers have made a surprising discovery about the role of a key molecule involved in pain in worms, and have built a structural model of the molecule. These discoveries, described Sept. 2 in Nature Communications, may help direct new strategies to treat pain in people.
In humans and other mammals, a family of molecules called TRP ion channels plays a crucial role in nerve cells that directly sense painful stimuli. Researchers are now blocking these channels in clinical trials to evaluate this as a possible treatment for various types of pain.
The roundworm Caenorhabditis elegans also expresses TRP channels — one of which is called OSM-9 — in its single head pain-sensing neuron (which is similar to the pain-sensing nerve cells for the human face). OSM-9 is not only vital for detecting danger signals in the tiny worms, but is also a functional match to TRPV4, a mammalian TRP channel involved in sensing pain.
In the new study, researchers created a series of genetic mutant worms in which parts of the OSM-9 channel were disabled or replaced and then tested the engineered worms’ reactions to overly salty solution, which is normally aversive and painful.
Specifically, the mutant worms had alterations in the pore of the OSM-9 channels in their pain-sensing neuron, which gets fired up upon channel activation to allow calcium and sodium to flow into the neuron. That, in turn, was thought to switch on the neural circuit that encodes rapid withdrawal behavior — like pulling the finger from the stove.
“People strongly believed that calcium entering the cell through the TRP channel is everything in terms of cellular activation,” said lead author Wolfgang Liedtke, M.D., Ph.D., an associate professor of neurology, anesthesiology and neurobiology at Duke University School of Medicine and an attending physician in the Duke Pain Clinics, where he sees patients with chronic head-neck and face-pain.
With then-graduate student Amanda Lindy, “we wanted to systemically mutagenize the OSM-9 pore and see what we could find in the live animal, in its pain behavior,” Liedtke said.
To the group’s surprise, changing various bits of OSM-9’s pore did not change most of the mutant worms’ reactions to the salty solution. However, these mutations did affect the flow of calcium into the cell. The disconnect they saw suggested the calcium was not playing a direct role in the worms’ avoidance of danger signals.
Calcium has been thought to be indispensable for pain behavior — not only in worms’ channels but in pain-related TRP channels in mammals. So results from the engineered OSM-9 mutant worms will change a central concept for the understanding of pain, Liedtke said.
To see whether calcium might instead play a role in the worms’ ability to adapt to repeated painful stimuli, the group then repeatedly exposed pore-mutant worms to the aversive and pain stimuli.
After the tenth trial, a normal worm becomes less sensitive to high salt. But one mutant worm with a minimal change to one specific part of its OSM-9 pore — altered so that calcium no longer entered but sodium did — was just as sensitive on the tenth trial as on the first.
The results confirmed that calcium flow through the channel makes the worms more adaptable to painful stimuli; it helps them cope with the onslaught by desensitizing them. This could well represent a survival advantage, Liedtke said.
To put the findings into a structural context, Liedtke collaborated with computational protein scientists Damian van Rossum and Andriy Anishkin from Penn State University, who built a structural model of OSM-9 that was based on established structures of several of the channel’s relatives, including the recently resolved structure of TRPV1, the molecule that senses pain caused by heat and hot chili peppers.
The team was then able to visualize the key parts of the OSM-9 pore in the context of the entire channel. They understood better how the pore holds its shape and allows sodium and calcium to pass.
Liedtke said that understanding this structure could be a great help in designing compounds that will not completely block the channel but will just prevent calcium from entering the cell. Although calcium helps desensitize worms to painful stimuli in the near term, it might set up chronic, pathological pain circuits in the long term, Liedtke said.
So, as a next step, the group plans to assess the longer-term effects calcium flow has in pain neurons. For example, calcium could change the expression of particular genes in the sensory neuron. And such gene expression changes could underlie chronic, pathologic pain.
“We assume, and so far the evidence is quite good, that chronic, pathological pain has to do with people’s genetic switches in their sensory system set in the wrong way, long term. That is something our new worm model will now allow us to approach rationally by experimentation,” Liedtke said.
This work was supported by the Esther A. and Joseph Klingenstein Fund, the Whitehall Foundation, start-up funds from Duke University, and grants from the National Science Foundation and the National Institutes of Health.
CITATION: “TRPV-channel-mediated calcium-transients in nociceptor neurons are dispensable for avoidance behavior,” Amanda S. Lindy, Puja K. Parekh, Richard Zhu, Patrick Kanju, Sree V. Chintapalli, Volodymyr Tsvilovskyy, Randen L. Patterson, Andriy Anishkin, Damian B. van Rossum, Wolfgang B. Liedtke. Nature Communications, Sept. 2, 2014
AVIAN INFLUENZA VIRUS ISOLATED IN HARBOR SEALS POSES A THREAT TO HUMANS
St. Jude Children’s Research Hospital-led study found naturally acquired mutations in the avian H3N8 flu virus allow the infection to spread in mammals via respiratory droplets; human immunity to the virus is lacking
From FMS Global News Desk of Jeanne Hambleton Released: 4-Sep-2014
Source Newsroom: St. Jude Children’s Research Hospital Citations Nature Communications
Newswise — (MEMPHIS, Tenn. – September 4, 2014) A study led by St. Jude Children’s Research Hospital scientists found the avian influenza A H3N8 virus that killed harbor seals along the New England coast can spread through respiratory droplets and poses a threat to humans. The research appears in the current issue of the scientific journal Nature Communications.
The avian H3N8 virus was isolated by scientists investigating the 2011 deaths of more than 160 harbor seals. Researchers discovered the virus had naturally acquired mutations in a key protein that previous laboratory research had shown allowed the highly pathogenic avian H5N1 virus to spread though respiratory droplets. Scientists reported that the avian H3N8 seal virus infected and grew in human lung cells.
Researchers also found that the virus spread in ferrets though respiratory transmission, which is uncommon for avian flu viruses and raises concerns about possible person-to-person airborne spread of the harbor seal virus. Investigators found no evidence of human immunity to the strain.
“This study highlights a gain-of-function experiment that occurred in nature and shows us there are avian flu viruses out there beyond H5N1 and H7N9 that could pose a threat to humans,” said corresponding author Stacey Schultz-Cherry, Ph.D., a member of the St. Jude Department of Infectious Diseases. In recent years, human cases of highly pathogenic avian H5N1 and H7N9 flu have been confirmed in countries around the world, with mortality rates approaching 60 percent.
“Avian H3N8 viruses are established in horses and dogs. This study raises a red flag about the threat this strain poses to humans exposed to animals infected with the virus,” Schultz-Cherry said. While no human illness was linked to the 2011 harbor seal virus, a different flu virus has spread from infected seals to humans who came in close contact with the animals. Avian H3N8 is also believed to have triggered a human flu pandemic in the 1880s.
The findings reinforce the need for continued surveillance of flu viruses circulating in wild and domestic animals to understand the risk the viruses pose to humans, said the study’s first author Erik Karlsson, Ph.D., a St. Jude postdoctoral fellow.
The H3N8 harbor seal virus caught the attention of researchers when sequencing showed the virus included two particular mutations in the hemagglutinin (HA) protein and a change in the PB2 gene. HA is carried on the surface of the flu virus. The virus depends on HA to bind to and infect cells. The PB2 mutation was associated with more severe illness in mice.
The HA and PB2 changes were among a handful of genetic alterations that in 2012 other scientists reported were sufficient to allow the highly pathogenic H5N1 to spread in ferrets via respiratory droplets.
In this study, two of the three animals exposed to the harbor seal virus via respiratory transmission became infected, although symptoms were mild.
Airborne transmission did not occur with the five other avian viruses tested, but two of the viruses spread in ferrets that shared cages. Both viruses were close genetic relatives of the harbor seal virus. Scientists want to understand the genetic changes that make respiratory transmission of avian H3N8 virus possible and the likelihood that related flu viruses will or have acquired those alterations.
Researchers also checked blood samples from 102 individuals vaccinated against seasonal flu strains between 2009 and 2011, including the human H3N2 flu strain. There was no evidence that seasonal flu vaccines protected against the harbor seal virus.
“The transmissibility of the seal H3N8 virus coupled with the apparent lack of immunity makes this strain a concern,” researchers noted.
The study’s other St. Jude authors are Richard Webby and Sun Woo Yoon and Jordan Johnson, both formerly of St. Jude. The other authors are Hon S Ip and Jeffrey Hall, of the U.S. Geological Survey (USGS), National Wildlife Health Center, Madison, Wis., and Melinda Beck of the University of North Carolina, Chapel Hill.
The study was funded in part by contracts from the National Institutes of Allergy and Infectious Diseases, which is part of the National Institutes of Health (NIH); grants from NIH; USGS and ALSAC.
St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children.
Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20 percent to 80 percent since the hospital opened more than 50 years ago.
St. Jude is working to increase the overall survival rate for childhood cancer to 90 percent in the next decade. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food—because all a family should worry about is helping their child live.
CALIFORNIA BLUE WHALES REBOUND FROM WHALING; FIRST OF THEIR KIN TO DO SO
From the FMS Global News Desk of Jeanne Hambleton 5-Sep-2014 Citations Marine Mammal Science Sept. 5, 2014; PLOS One Source Newsroom: University of Washington
Newswise — The number of California blue whales has rebounded to near historical levels, according to new research by the University of Washington, and while the number of blue whales struck by ships is likely above allowable U.S. limits, such strikes do not immediately threaten that recovery.
This is the only population of blue whales known to have recovered from whaling – blue whales as a species having been hunted nearly to extinction.
Blue whales – nearly 100 feet in length and weighing 190 tons as adults – are the largest animals on earth. And they are the heaviest ever, weighing more than twice as much as the largest known dinosaur, the Argentinosaurus. They are an icon of the conservation movement and many people want to minimize harm to them, according to Trevor Branch, UW assistant professor of aquatic and fishery sciences.
“The recovery of California blue whales from whaling demonstrates the ability of blue whale populations to rebuild under careful management and conservation measures,” said Cole Monnahan, a UW doctoral student in quantitative ecology and resource management and lead author of a paper on the subject posted online Sept. 5 by the journal Marine Mammal Science. Branch and André Punt, a UW professor of aquatic and fisheries sciences, are co-authors.
California blue whales ¬ are at their most visible while at feeding grounds 20 to 30 miles off the California coast, but are actually found along the eastern side of the Pacific Ocean from the equator up into the Gulf of Alaska.
Today they number about 2,200, according to monitoring by other research groups. That is likely 97 percent of the historical level according to the model the co-authors used. That may seem to some a surprisingly low number of whales, Monnahan said, but not when considering how many California blue whales were caught. According to new data Monnahan, Branch and another set of co-authors published earlier this summer in PLOS ONE, approximately 3,400 California blue whales were caught between 1905 and 1971.
“Considering the 3,400 caught in comparison to the 346,000 caught near Antarctica gives an idea how much smaller the population of California blue whales was likely to have been,” Branch said.
The catches of blue whales from the North Pacific were unknown until scientists – in particular Yulia Ivashchenko of Southern Cross University in Australia – put on their detective caps and teased out numbers from Russian whaling archives that once were classified as secret but are now public. The numbers Russian whalers had publicly reported at one time were incomplete and inaccurate ¬– something that was admitted in the late 1990s – but there was not access to the real numbers until recently.
For the work published in PLOS ONE, the scientists then used acoustic calls produced by the whales to separate – for the first time – the catches taken from the California population from those whales taken in the western Northern Pacific near Japan and Russia. The two populations are generally accepted by the scientific community as being different. Places where acoustic data indicated one group or the other is present were matched with whaling catches.
In the subsequent Marine Mammal Science paper just out, the catches were among the key pieces of information used to model the size of the California blue whale population over time – a model previously used by other groups to estimate populations of hundreds of fish and various other whale species.
The population returning to near its historical level explains the slowdown in population growth, noted in recent years, better than the idea of ship strikes, the scientists said.
There are likely at least 11 blue whales struck a year along the U.S. West Coast, other groups have determined, which is above the “potential biological removal” of 3.1 whales per year allowed by the U.S. Marine Mammal Protection Act.
The new findings says there could be an 11-fold increase in vessels before there is a 50 percent chance that the population will drop below what is considered “depleted” by regulators.
“Even accepting our results that the current level of ship strikes is not going to cause overall population declines, there is still going to be ongoing concern that we do not want these whales killed by ships,” Branch said.
Without ship strikes as a big factor holding the population back – and no other readily apparent human-caused reason (although noise, chemical pollution and interactions with fisheries may impact them) – it is even more likely that the population is growing more slowly because whale numbers are reaching the habitat limit, something called the carrying capacity.
“We think the California population has reached the capacity of what the system can take as far as blue whales,” Branch said.
“Our findings are not meant to deprive California blue whales of protections that they need going forward,” Monnahan said.
“California blue whales are recovering because we took actions to stop catches and start monitoring. If we had not, the population might have been pushed to near extinction – an unfortunate fate suffered by other blue whale populations.”
“It is a conservation success story,” Monnahan said.
Funding for students working on the research in Branch’s lab comes through the Joint Institute for the Study of the Atmosphere and Ocean, a collaboration between the National Oceanic and Atmospheric Administration and UW.
I love stories with a happy endings. These are such magnificent creatures and we owe them a great deal of respect. A London double decker bus is 36ft. 5 inches. When three come along together, as they sometimes do, that is like a blue Whale arriving and filling the road. Think about that the next time you get on a double decker bus. The average blue whale is 100ft. and 190 tons. It takes a bit of imagination. I now know what my friends mean when they say,”Have a ‘whale’ of a time!” That gives you an awful lot of latitude to enjoy yourself. Such good news to hear they are on the rebound. Back soon Jeanne