New insight on inflammatory regulation could inform future pain drug development

December 18, 2018

A novel way in which the inflammatory response to pain is regulated has been described in the open-access journal eLife.

The results add to our understanding of the mechanisms that cause increased sensitivity to pain in response to injury and inflammation, and could pave the way for more effective therapies.

Inflammatory hyperalgesia, the hypersensitivity to thermal and chemical stimuli, can be divided into two phases - acute and chronic. As part of this condition, inflammatory mediators, including growth factors, stimulate and sensitise pain receptors. A protein that also plays a key role here is Transient Receptor Potential Vanilloid Subtype 1 (TRPV1).

Nerve growth factor (NGF) is also involved in inflammatory hyperalgesia and, in chronic pain, produces changes in the protein expression of TRPV1. "It has been known for over a decade that NGF sensitises pain-receptor neurons through increased trafficking of TRPV1 channels to the cell surface, and that this sensitisation requires the activation of an enzyme called phosphoinositide 3-kinase, or PI3K," explains first author Anastasiia Stratiievska, PhD candidate in the Department of Physiology and Biophysics at the University of Washington, Seattle, US. "But the mechanism by which this occurs was still unknown, and we wanted to gather more insights into the process."

To do this, Stratiievska and her team used an imaging technique called two-colour total internal reflection fluorescence microscopy to study TRPV1-expressing cells. Their analysis revealed that TRPV1 increased PI3K activity. Although TRPV1 is a large, multi-domain protein embedded in the cell surface, a small fragment of the protein called the ARD was enough to cause this increase in activity.

"Because the ARD is structurally conserved among TRPV channels, we tested whether other channels besides TRPV1 could increase NGF-induced PI3K activity," says senior author Sharona Gordon, Professor of Physiology and Biophysics at the University of Washington, Seattle. "We saw that this was indeed also true for TRPV2 and TRPV4."

"Together, our findings reveal a previously unknown reciprocal regulation among multiple TRPV channels and PI3K," Stratiievska concludes. "The next steps will be to identify ARD mutations that prevent this regulation. It would also be interesting to determine the exact role that reciprocal regulation plays in sensitisation to painful stimuli within model organisms, as this could help with the development of more effective painkillers further down the line."
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Reference

The paper 'Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor' can be freely accessed online at https://doi.org/10.7554/eLife.38869. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

Media contact

Emily Packer, Senior Press Officer
eLife
e.packer@elifesciences.org
01223 855373

About eLife

eLife aims to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science. We publish important research in all areas of the life and biomedical sciences, including Biochemistry and Chemical Biology, and Structural Biology and Molecular Biophysics, which is selected and evaluated by working scientists and made freely available online without delay. eLife also invests in innovation through open-source tool development to accelerate research communication and discovery. Our work is guided by the communities we serve. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, the Wellcome Trust and the Knut and Alice Wallenberg Foundation. Learn more at https://elifesciences.org/about.

To read the latest Biochemistry and Chemical Biology research published in eLife, visit https://elifesciences.org/subjects/biochemistry-chemical-biology.

For our latest Structural Biology and Molecular Biophysics research, visit https://elifesciences.org/subjects/structural-biology-molecular-biophysics.

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