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Elife. 2018 Dec 18;7. pii: e38869. doi: 10.7554/eLife.38869.

Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor.

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Department of Physiology and Biophysics, University of Washington, Seattle, United States.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
Department of Pediatrics and Graduate Program in Neuroscience, University of Washington, Seattle, United States.


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 two-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.


NGF; PI3K; PIP3; TRPV1; TRPV2; biochemistry; chemical biology; inflammation; molecular biophysics; none; structural biology

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