Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor
- University of Washington, United States
- Seattle Children's Research Institute, United States
Abstract
Although it has been known for over a decade that the inflammatory mediator NGF sensitizes pain-receptor neurons through increased trafficking of TRPV1 channels to the plasma membrane, the mechanism by which this occurs remains mysterious. NGF activates phosphoinositide 3-kinase (PI3K), the enzyme that generates PI(3,4)P2 and PIP3, and PI3K activity is required for sensitization. One tantalizing hint came from the finding that the N-terminal region of TRPV1 interacts directly with PI3K. Using 2-color total internal reflection fluorescence microscopy, we show that TRPV1 potentiates NGF-induced PI3K activity. A soluble TRPV1 fragment corresponding to the N-terminal Ankyrin repeats domain (ARD) was sufficient to produce this potentiation, indicating that allosteric regulation was involved. Further, other TRPV channels with conserved ARDs also potentiated NGF-induced PI3K activity. Our data demonstrate a novel reciprocal regulation of PI3K signaling by the ARD of TRPV channels.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Eye Institute (R01EY017564)
- Sharona E Gordon
National Institute of General Medical Sciences (R01GM100718)
- Sharona E Gordon
National Institute of General Medical Sciences (R01GM125351)
- Sharona E Gordon
University of Washington (Royalty Research Fund)
- Sharona E Gordon
National Institute of Mental Health (R01MH113545)
- Stephen EP Smith
National Institute of Biomedical Imaging and Bioengineering (T32EB001650)
- Anastasiia Stratiievska
National Institutes of Health (S10RR025429)
- Sharona E Gordon
National Institutes of Health (P30DK017047)
- Sharona E Gordon
National Institutes of Health (P30EY001730)
- Sharona E Gordon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Stratiievska et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor
eLife 7:e38869.
https://doi.org/10.7554/eLife.38869
