The Big Pore Theory could cure chronic pain

April 14, 2017 by Elodie Gazave, Cornell University

Cornell University researchers have produced for the first time an image of P2X7, a receptor associated with chronic pain. Visualizing the shape of the receptor has also allowed them to make a second groundbreaking discovery: They observed that five painkiller molecules they tested did not bind the receptor at the place they expected, which could explain why these painkillers lack efficacy in human patients.

This discovery, published Dec. 9, 2016, in the journal eLife, lays the foundations to create targeted and effective to manage .

Chronic pain affects 10 percent of the adult population. It also accompanies conditions such as rheumatoid arthritis and migraine, for which pain management remains crucial in patient care. However, chronic pain does not always respond to existing analgesic drugs.

The lack of effective medicines is partly due to the limited knowledge scientists have about pain. Cornell researchers have been looking into a receptor called P2X7, which binds a molecule called ATP.

Many drugs targeting P2X7 work by competing for space with the ATP molecule, occupying the groove at the surface of P2X7 where ATP would naturally bind. Scientist believe that preventing ATP from binding to the P2X7 receptor should block the pain signal.

Research in animal models had shown promising results for drugs targeting P2X7. However, clinical trials in humans were much less satisfactory.

To understand why these trials failed in humans, a team led by Toshimitsu Kawate, assistant professor in the College of Veterinary Medicine's Department of Molecular Medicine, decided to visualize the shape of the receptor. The results were astonishing, he said: "The drugs were not where we expected them to bind. We were actually shocked."

To make this discovery, Kawate and his team had to see the structure of the receptor. Using X-ray crystallography at the Cornell High Energy Synchrotron Source (CHESS), Kawate created an image of the receptor at a resolution of 3.5 angstroms – about a thousandth of the width of hair.

They found that P2X7 is an "elegant" molecule comprising three dolphin-shaped subunits. The "dolphin's fluke" of the three subunits is anchored in the . These flukes work as a "camera shutter" that can twist open or close – a motion triggered by ATP.

In absence of ATP, the flukes form a closed conformation. When ATP molecules bind to the dolphin's upper body, the flukes rotate in a spiraling motion and form a in the cell membrane, allowing water, ions and other small molecules to pass through.

P2X7 has one interesting particularity compared with other ion-channel proteins. It mainly functions as a normal pore, but sometimes it converts into a big pore and allows molecules up to 900 dalton, a unit that quantifies mass at atomic levels, through the membrane.

This big pore conversion process is what Kawate wants to study next to learn why and how frequently big pore conversion happens. Some theorize that under pathological conditions, big pore conformation might be what creates pain. For example, pain-causing molecules could be released from inside the cell to the surrounding tissues through the P2X7 channel. Kawate is trying to design genetic or chemical traps to capture P2X7 big pores so that he can visualize the structure and understand their biological significance.

Understanding under which physiological conditions and how the conversion happens may help manipulate the receptor, for example to design that can trap P2X7 and prevent its conversion to a big pore state. "This could be useful to treat several types of chronic , for example associated with irritable bowel syndrome, that are proposed to be caused by the big pore of P2X7."

Explore further: Study suggests new way to treat chronic pain

More information: Akira Karasawa et al. Structural basis for subtype-specific inhibition of the P2X7 receptor, eLife (2016). DOI: 10.7554/eLife.22153

Related Stories

Study suggests new way to treat chronic pain

March 26, 2012
Nearly one in five people suffers from the insidious and often devastating problem of chronic pain.

Research sheds new light on how blood clots form

June 13, 2011
Scripps Research Institute scientists have discovered new elements of the blood clot-formation process. The findings could lead to better drugs for preventing heart attacks and other clot-related conditions.

Scientists reveal non-addictive pathway to pain relief

January 12, 2017
OHSU research suggests an avenue for developing treatments for chronic pain that harness the medicinal properties of cannabis while minimizing the threat of addiction.

Researchers develop computer simulation of body's heat response

September 20, 2016
For the first time, scientists at the M.M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences have successfully used computer-generated simulations to study the TRPV1-receptor ...

Naturally occurring protein has a role in chronic pain

June 12, 2012
Researchers in France and Sweden have discovered how one of the body's own proteins is involved in generating chronic pain in rats. The results, which also suggest therapeutic interventions to alleviate long-lasting pain, ...

Recommended for you

Breakthrough article on mechanistic features of microRNA targeting and activity

March 23, 2018
Giovanna Brancati and Helge Grosshans from the FMI have described target specialization of miRNAs of the let-7 family. They identified target site features that determine specificity, and revealed that specificity can be ...

Boosting enzyme may help improve blood flow, fitness in elderly

March 22, 2018
As people age, their blood-vessel density and blood flow decrease, which is why it's harder to maintain muscle mass after 40 and endurance in the later decades, even with exercise. This vascular decline is also one of the ...

Scientists pinpoint cause of vascular aging in mice

March 22, 2018
We are as old as our arteries, the adage goes, so could reversing the aging of blood vessels hold the key to restoring youthful vitality?

Sulfur amino acid restriction diet triggers new blood vessel formation in mice

March 22, 2018
Putting mice on a diet containing low amounts of the essential amino acid methionine triggered the formation of new blood vessels in skeletal muscle, according to a new study from Harvard T.H. Chan School of Public Health. ...

Cold can activate body's 'good' fat at a cellular level, study finds

March 21, 2018
Lower temperatures can activate the body's 'good' fat formation at a cellular level, a new study led by academics at The University of Nottingham has found.

Gradual release of immunotherapy at site of tumor surgery prevents tumors from returning

March 21, 2018
A new study by Dana-Farber Cancer Institute scientists suggests it may be possible to prevent tumors from recurring and to eradicate metastatic growths by implanting a gel containing immunotherapy during surgical removal ...


Adjust slider to filter visible comments by rank

Display comments: newest first

1 / 5 (1) Apr 16, 2017
Cornell might consult their butterfly pheromone chemists on this. This looks like a pheromone receptor protein. Synergistic species specific reception of multicomponent mixtures of pheromone stereochemistry would diminish chronic pain. Try 250mg of healthy adult male facial skin surface lipid pheromone (usually passed in innocent kissing). It has 735 components and their delivery in social behavior would reward socially appropriate behavior. Heroes should get lots of kisses anyway! They need them.
5 / 5 (1) Apr 16, 2017
"Synergistic species specific reception of multicomponent mixtures of pheromone stereochemistry would diminish chronic pain. Try 250mg of healthy adult male facial skin surface lipid pheromone (usually passed in innocent kissing). It has 735 components . "
- cite your source(s) please.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.